2-aryl- and 2-heteroaryl-substituted 2-pyridazin-3(2h)-one compounds as inhibitors of fgfr tyrosine kinases

ABSTRACT

and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which X, R1, R2, R3, Ring A and z have the meanings given in the specification, which are inhibitors of FGFR1, FGFR2, FGFR3 and/or FGFR4 and are useful in the treatment and prevention of diseases which can be treated with an FGFR inhibitor, including diseases or disorders mediated by FGFR1, FGFR2, FGFR3 and/or FGFR4.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent Ser. No. 15/333,148,filed Oct. 24, 2016, which claims the benefit of U.S. ProvisionalApplication No. 62/245,956, filed on Oct. 23, 2015, which areincorporated herein by reference in their entirety.

BACKGROUND

The present disclosure relates to novel compounds which exhibitinhibition of fibroblast growth factor receptor tyrosine kinases(FGFRs), in particular FGFR1, FGFR2, FGFR3 and/or FGFR4, pharmaceuticalcompositions comprising the compounds, to processes for making thecompounds, and the use of the compounds in therapy. More particularly,it relates to 2-aryl- and 2-heteroaryl-substituted 2-pyridazin-3(2H)-onecompounds useful in the treatment or prevention of diseases which can betreated with an FGFR inhibitor, including diseases mediated by FGFRtyrosine kinases.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate awide range of physiologic cellular processes, such as embryonicdevelopment, differentiation, proliferation, survival, migration, andangiogenesis.

The FGF family comprises 18 secreted ligands (FGFs) which are readilysequestered to the extracellular matrix by heparin sulfate proteoglycans(HPSGs). For signal propagation, FGFs are released from theextracellular matrix by proteases or specific FGF-binding proteins, withthe liberated FGFs subsequently binding to a cell surface FGF-receptor(FGFR) in a ternary complex consisting of FGF, FGFR and HPSG (Beenken,A., Nat. Rev. Drug Discov. 2009; 8:235-253).

There are five FGFRs, of which four (FGFRs 1-4) are highly conservedsingle-pass transmembrane tyrosine kinase receptors (Eswarakumar, V. P.,Cytokine Growth Factor Rev., 2005; 16:139-149). The binding of an FGF toan FGFR leads to receptor dimerization and transphosphorylation oftyrosine kinase domains (Dieci, M. V., et al., Cancer Discov. 2013;3:264-279; Korc, N., and Friesel, R. E., Curr. Cancer Drug Targets 2009;5:639-651). Activation of downstream signaling occurs via theintracellular receptor substrate FGFR substrate 2 (FRS2) andphospholipase Cγ (PLC-γ), leading to subsequent upregulation ofRAS/mitogen-activated protein kinase (MAPK) and phosphoinositide3-kinase (PI3K)/AKT signaling pathways. Other pathways can be activated,including STAT-dependent signaling (Turner, N., Grose, R., Nat. Ref.Cancer 2010; 10:116-129; Brooks, N. S., et al., Clin Cancer Res. 2012;18:1855-1862; Dienstmann, R., et al., Ann. Oncol. 2014; 25:552-563).

FGFR signaling components are frequently altered in human cancer, andseveral preclinical models have provided compelling evidence for theoncogenic potential of aberrant FGFR signaling in carcinogenesis,thereby validating FGFR signaling as an attractive target for cancertreatment.

The mechanisms by which FGFR signaling is dysregulated and drive cancerare better understood in recent years, and include activating mutations,FGFR gene amplification, chromosomal translocations, autocrine andparacrine signaling, and altered FGFR splicing.

SUMMARY OF THE INVENTION

It has now been found that 2-aryl- and 2-heteroaryl-substituted2-pyridazin-3(2H)-one compounds are inhibitors of FGFR1, FGFR2, FGFR3and/or FGFR4, which are useful in the treatment or prevention ofdiseases which can be treated with an inhibitor of FGFR1, FGFR2, FGFR3and/or FGFR4, including diseases mediated by FGFR1, FGFR2, FGFR3 and/orFGFR4.

Accordingly, provided herein is a compound of the general Formula I:

or pharmaceutically acceptable salt or solvate thereof, wherein X, RingA, z, R¹, R² and R³ are as defined herein.

Also provided herein is a pharmaceutical composition comprising acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, in admixture with a pharmaceutically acceptable diluent orcarrier.

Also provided herein is a method of inhibiting cell proliferation, invitro or in vivo, the method comprising contacting a cell with aneffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositionthereof as defined herein.

Also provided herein is a method of treating an FGFR-associated diseaseor disorder in a patient in need of such treatment, the methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof, or a pharmaceutical composition thereof as definedherein.

Also provided herein is a method of treating cancer and/or inhibitingmetastasis associated with a particular cancer in a patient in need ofsuch treatment, the method comprising administering to the patient atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof as defined herein.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositionthereof as defined herein for use in therapy.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof as defined herein for use in the treatment of cancer and/orinhibiting metastasis associated with a particular cancer.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof for use in the inhibition of FGFR1,FGFR2, FGFR3 and/or FGFR4.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof as defined herein, for use in the treatment of anFGFR-associated disease or disorder.

Also provided herein is the use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for the treatment of cancer and/orinhibiting metastasis associated with a particular cancer.

Also provided herein is a use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for the inhibition of activity ofFGFR1, FGFR2 FGFR3 and/or FGFR4.

Also provided herein is the use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, as defined herein,in the manufacture of a medicament for the treatment of anFGFR-associated disease or disorder.

Also provided herein is a method for treating cancer in a patient inneed thereof, the method comprising (a) determining if the cancer isassociated with a dysregulation of an FGFR gene, a fibroblast growthfactor receptor, or expression or activity or level of any of the same(e.g., an FGFR-associated cancer); and (b) if the cancer is determinedto be associated with a dysregulation of an FGFR gene, a fibroblastgrowth factor receptor, or expression or activity or level of any of thesame (e.g., an FGFR-associated cancer), administering to the patient atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition thereof.

Also provided herein is a method for reversing or preventing acquiredresistance to an anticancer drug, comprising administering atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, to a patient atrisk for developing or having acquired resistance to an anticancer drug.In some embodiments, the patient is administered a dose of theanticancer drug (e.g., at substantially the same time as a dose of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof is administered to the patient).

Also provided herein is a method of delaying and/or preventingdevelopment of cancer resistant to an anticancer drug in an individual,comprising concomitantly administering to the individual (a) aneffective amount of a compound of Formula I and (b) an effective amountof the anticancer drug.

Also provided herein is a method of treating an individual with cancerwho has increased likelihood of developing resistance to an anticancerdrug, comprising concomitantly administering to the individual (a) aneffective amount of a compound of Formula I and (b) an effective amountof the anticancer drug.

Also provided herein is a method for treating a disease involvingangiogenesis and/or neovascularization, comprising administering to asubject in need thereof, a therapeutically effective amount of acompound of Formula I.

Also provided herein is a method for inhibiting angiogenesis in a tumor,which comprises contacting the tumor with a compound of Formula I.

Also provided herein is a pharmaceutical combination for treating cancerin a patient in need thereof, which comprises (a) a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof, (b) anadditional therapeutic agent, and (c) optionally at least onepharmaceutically acceptable carrier, for simultaneous, separate orsequential use for the treatment of cancer, wherein the amounts of thecompound of Formula I or pharmaceutically acceptable salt or solvatethereof and of the additional therapeutic agent are together effectivein treating the cancer. Also provided herein is a pharmaceuticalcomposition comprising such a combination. Also provided herein is theuse of such a combination for the preparation of a medicament for thetreatment of cancer. Also provided herein is a commercial package orproduct comprising such a combination as a combined preparation forsimultaneous, separate or sequential use; and to a method of treatmentof cancer a patient in need thereof.

Also provided herein is a process for preparing a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof obtained by a process of preparingthe compound as defined herein.

In some embodiments, a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof exhibits potent and selective FGFRinhibition. In some embodiments, said inhibition occurs with relativesparing of FGFR1 inhibition. In certain embodiments, a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereofexhibits a relatively high potency for FGFR2 and FGFR3 (e.g., FGFR3,e.g., FGFR3-TACC3 fusion). In certain embodiments, a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof providesdose-dependent inhibition of tumor growth in RT112/84 FGFR3-TACC3xenografts. In certain embodiments, a compound of Formula I or apharmaceutically acceptable salt or solvate thereof exhibits(independently) greater selectivity for FGFR2 and/or FGFR3 (e.g., FGFR3)as compared to FGFR1 (e.g., exhibits greater selectivity for FGFR3 overFGFR1 in enzyme and cell-based assays e.g., exhibit greater cytotoxicityfor FGFR2/3 than FGFR1 mutant cells). See Lewin, et al, Journal ofClinical Oncolgy, 2015, 22, 3372.

In some embodiments, administration of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof results in lesshyperphosphatemia than administration of a pan-FGFR inhibitor (e.g., apan-FGFR inhibitor, which when compared with the Formula I compoundsdescribed herein, exhibits less selectivity for FGFR2 and/or FGFR3(e.g., FGFR3) as compared to FGFR1; e.g., a pan-FGFR inhibitor that isless sparing of FGFR1 inhibition than the Formula I compounds describedherein). In view of the foregoing and while not wishing to be bound bytheory, it is believed that a compound of Formula I or apharmaceutically acceptable salt or solvate thereof can provide greaterdosing/regimen flexibility and/or efficacy than, for example, a pan-FGFRinhibitor (e.g., a pan-FGFR inhibitor, which when compared with theFormula I compounds described herein, exhibits less selectivity forFGFR2 and/or FGFR3 (e.g., FGFR3) as compared to FGFR1; e.g., a pan-FGFRinhibitor that is less sparing of FGFR1 inhibition than the Formula Icompounds described herein). By way of example, and as the skilledperson will appreciate, the compounds described herein can beadministered at higher doses and/or with increased frequencies, therebyproviding higher drug exposure/target coverage, and done so with reducedrisk of causing unwanted (e.g., abnormal) increases in blood phosphatelevels, which in some instances can necessitate administration ofphosphate binders and/or temporary (e.g., drug holidays) or permanentcessation of therapy to allow phosphate levels to return to normal.

Accordingly, also provided are methods of treating a FGFR-associatedcancer in a patient, which include: (a) administering to a patientidentified or diagnosed as having an FGFR-associated cancer one or moredoses of a first FGFR inhibitor over a treatment period; (b) determiningthe level of phosphate in a biological sample comprising blood, serum,or plasma obtained from the patient after the treatment period; (c)selecting a patient having an elevated level of phosphate in thebiological sample as compared to a reference level of phosphate; and (d)ceasing administration of the first FGFR inhibitor and initiatingadministration of a therapeutically effective amount of a compound asdescribed herein or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition containing the same, to theselected patient. In certain embodiments, the treatment period is atleast 7 days. In other embodiments, the treatment period is at least 21days. In certain embodiments, the first FGFR inhibitor is JNJ-42756493or BGJ398. By way of example, the first FGFR inhibitor can beJNJ-42756493 and a daily dose of 6 mg to 12 mg of the first FGFRinhibitor is administered to the patient over the treatment period(e.g., 7 days). As another example, the first FGFR inhibitor can beBGJ398 and a daily dose of 50 mg to 125 mg of the first FGFR inhibitoris administered to the patient over the treatment period (e.g., 21days). In certain embodiments, the patient is administered atherapeutically effective amount of a phosphate binder over thetreatment period. In certain embodiments, step (d) further comprisesceasing administration of the phosphate binder to the selected patient.In certain embodiments, step (d) further includes administering adecreased dose of the phosphate binder to the selected patient relativeto the dose of the phosphate binder administered to the patient over thetreatment period. JNJ-42756493 (erdafitinib) is also known as JNJ-493and has the following systematic name,N1-(3,5-dimethoxyphenyl)-N2-isopropyl-N1-(3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)ethane-1,2-diamine,and the following structure:

BGJ398 (infigratinib) has the following systematic name,3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea,and the following chemical structure:

Also provided herein are methods of treating a FGFR-associated cancer ina patient, the method comprising administering a therapeuticallyeffective dose of a compound as described herein or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositioncontaining the same to a patient identified or diagnosed as having anFGFR-associated cancer over a treatment period of at least 8 days,wherein the patient is determined to have about the same or a decreasedlevel of phosphate in one or more biological sample(s) comprising blood,serum, or plasma obtained from the patient over the treatment period ascompared to a reference level of phosphate.

Also provided herein are methods of treating a FGFR-associated cancer ina patient, the method comprising administering a therapeuticallyeffective dose of a compound as described herein or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositioncontaining the same to a patient identified or diagnosed as having anFGFR-associated cancer over a treatment period, wherein the patient isnot administered a phosphate binder over the treatment period.

Also provided herein are methods of treating a FGFR-associated cancer ina patient, the method comprising administering a therapeuticallyeffective dose of a compound as described herein or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositioncontaining the same to a patient identified or diagnosed as having anFGFR-associated cancer over a treatment period, wherein the patient isfurther administered a low dose of a phosphate binder over the treatmentperiod.

Also provided herein are methods of treating a patient having aFGFR-associated cancer, the method comprising administering atherapeutically effective dose of a compound as described herein or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition containing the same to a patient identified or diagnosed ashaving an FGFR-associated cancer over a treatment period, wherein thepatient does not experience or is less likely to experience one or moreof soft tissue calcification, stomatitis, dry mouth, nail changes,fatigue, asthenia, anorexia, malaise, and muscle aches over thetreatment period.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein is a compound of the general Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is N or CH;

Ring A is a 5-membered heteroaryl ring having 1-2 ring nitrogen atoms;

z is 1, 2 or 3;

each R¹ is independently selected from the group consisting of:

(a) hydrogen,

(b) C1-C6 alkyl (optionally substituted with 1-3 fluoros),

(c) hydroxy(C1-C6 alkyl)- (optionally substituted with 1-3 fluoros),

(d) dihydroxy(C1-C6 alkyl)- (optionally substituted with 1-3 fluoros),

(e) cyano(C1-C6 alkyl)-,

(f) R^(a)R^(b)N(C1-C6 alkyl)-,

(g) (C1-C3 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3fluoros),

(h) (C3-C6 cycloalkyl)(CH₂)_(n)— where n is 0-3 and said cycloalkyl isoptionally substituted with CN, OH, R^(a)R^(b)N—, (1-3C)alkyl or(1-3C)alkoxy,

(i) hetCyc¹(CH₂)_(m)— where m is 0-3,

(j) hetCyc²(CH₂)_(p)— where p is 0 or 1,

(k) hetAr¹(CH₂)_(q)— where q is 1 or 2,

(l) halogen, and

(m) hetCyc¹C(═O)CH₂—;

hetCyc¹ is a 4-7 membered saturated heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of fluoro,HO, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R^(c)R^(d)N- and (C1-C6alkyl)C(═O)—;

hetCyc² is a 7-10 membered heterospirocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterospirocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl- (optionally substituted with 1-3 fluoros), (C3-C6cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R^(c)R^(d)N- and (C1-C6alkyl)C(═O)—;

hetAr¹ is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms,wherein said ring is optionally substituted with one or moresubstituents independently selected from C1-C6 alkyl and halogen;

R² is Ar¹ or hetAr²;

Ar¹ is phenyl substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—,(C1-C3 alkyl)C(═O)NH—, (cyclopropyl)C(═O)NH— and (cyclopropyl)NHC(═O)—,wherein each of said C1-C3 alkyl and C1-C3 alkoxy portions is optionallysubstituted with 1-3 fluoros;

hetAr² is a 6-10 membered heteroaryl ring having 1-2 ring nitrogenatoms, wherein said heteroaryl ring is optionally substituted with oneor more groups independently selected from halogen, C1-C3 alkyl, C1-C3alkoxy, (C1-C3 alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (C3-C4cycloalkyl)C(═O)NH— and (C3-C4 cycloalkyl)NHC(═O)—, wherein each of saidC1-C3 alkyl and C1-C3 alkoxy portions is optionally substituted with 1-3fluoros;

R³ is hydrogen, C1-C4 alkyl or (C3-C4)cycloalkyl; and

R^(a), R^(b), R^(c) and R^(d) are independently hydrogen or C1-C6 alkyloptionally substituted with F, OH or C1-C6 alkoxy.

In some embodiments of general formula (I):

X is N or CH;

Ring A is a 5-membered heteroaryl ring having 1-2 ring nitrogen atoms;

z is 1, 2 or 3;

each R¹ is independently selected from the group consisting of:

(a) hydrogen,

(b) C1-C6 alkyl (optionally substituted with 1-3 fluoros),

(c) hydroxy(C1-C6 alkyl)- (optionally substituted with 1-3 fluoros),

(d) dihydroxy(C1-C6 alkyl)- (optionally substituted with 1-3 fluoros),

(e) cyano(C1-C6 alkyl)-,

(f) R^(a)R^(b)N(C1-C6 alkyl)-,

(g) (C1-C3 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3fluoros),

(h) (C3-C6 cycloalkyl)(CH₂)_(n)— where n is 0-3 and said cycloalkyl isoptionally substituted with CN, OH, R^(a)R^(b)N—, (1-3C)alkyl or(1-3C)alkoxy,

(i) hetCyc¹(CH₂)_(m)— where m is 0-3,

(j) hetCyc²(CH₂)_(p)— where p is 0 or 1,

(k) hetAr¹(CH₂)_(q)— where q is 1 or 2, and

(1) halogen;

hetCyc¹ is a 4-7 membered saturated heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of fluoro,HO, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R^(c)R^(d)N- and (C1-C6alkyl)C(═O)—;

hetCyc² is a 7-10 membered heterospirocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterospirocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl- (optionally substituted with 1-3 fluoros), (C3-C6cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R^(c)R^(d)N- and (C1-C6alkyl)C(═O)—;

hetAr¹ is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms,wherein said ring is optionally substituted with one or moresubstituents independently selected from C1-C6 alkyl and halogen;

R² is Ar¹ or hetAr²;

Ar¹ is phenyl substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—,(C1-C3 alkyl)C(═O)NH—, (cyclopropyl)C(═O)NH— and (cyclopropyl)NHC(═O)—,wherein each of said C1-C3 alkyl and C1-C3 alkoxy portions is optionallysubstituted with 1-3 fluoros;

hetAr² is a 6 membered heteroaryl ring having 1-2 ring nitrogen atoms,wherein said heteroaryl ring is optionally substituted with one or moregroups independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy,(C1-C3 alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (C3-C4 cycloalkyl)C(═O)NH—and (C3-C4 cycloalkyl)NHC(═O)—, wherein each of said C1-C3 alkyl andC1-C3 alkoxy portions is optionally substituted with 1-3 fluoros;

R³ is hydrogen, C1-C4 alkyl or (C3-C4)cycloalkyl; and

R^(a), R^(b), R^(c) and R^(d) are independently hydrogen or C1-C6 alkyloptionally substituted with F, OH or C1-C6 alkoxy.

For complex chemical names employed herein, the substituent group isnamed before the group to which it attaches. For example, methoxyethylcomprises an ethyl backbone with a methoxy substituent.

The term “halogen” as used herein means —F (sometimes referred to hereinas “fluoro” or fluoros”), —Cl, —Br and —I.

The terms “C1-C3 alkyl” and “C1-C6 alkyl” as used herein refer to amonovalent, saturated linear or branched hydrocarbon chains having fromone to three and one to six carbon atoms, respectively. Examplesinclude, but are not limited to, methyl, ethyl, 1-propyl, isopropyl,1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl,pentan-3-yl and hexyl.

The term “hydroxy(C1-C6 alkyl)-” as used herein refers to a monovalent,saturated linear or branched hydrocarbon chain having from one to sixcarbon atoms, wherein any one of the carbon atoms is substituted with ahydroxy (—OH) group.

The terms “dihydroxy(C1-C6 alkyl)-” and “dihydroxy(C3-C6 alkyl)-” asused herein refers to a monovalent, saturated linear or branchedhydrocarbon chain having from one to six carbon atoms or three to sixcarbon atoms, respectively, wherein any two of the carbon atoms are eachsubstituted with a hydroxy group, provided that both hydroxy groups arenot attached to the same carbon atom.

The term “cyano(C1-C6 alkyl)-” as used herein refers to a monovalent,saturated linear or branched hydrocarbon chain having from one to sixcarbon atoms, wherein any one of the carbon atoms is substituted with acyano (—CN) group.

The terms “C1-C3 alkoxy” and “C1-C6 alkoxy” as used herein refer togroups that have the formula, —OR, wherein R is “C1-C3 alkyl” and “C1-C6alkyl”, respectively, as defined herein. Illustrative examples include,but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, and hexyloxy.

The term “(C1-C6 alkoxy)(C1-C6 alkyl)-” as used herein refers to amonovalent, saturated linear or branched hydrocarbon chain having fromone to six carbon atoms, wherein any one of the carbon atoms issubstituted with a C1-C6 alkoxy group as defined herein.

The term “C3-C6 cycloalkyl” refers to a monovalent, monocyclic,saturated hydrocarbon ring having from three to six ring atoms.Illustrative examples include, but are not limited to, cyclopropyl andcyclobutyl.

The term “C3-C6 cycloalkoxy” as used herein refers to a group having theformula, —OR′, wherein R′ is “C3-C6 cycloalkyl” as defined herein.

The term “(C3-C6 cycloalkoxy)C1-C6 alkyl-” as used herein refers to amonovalent, saturated linear or branched hydrocarbon chain having fromone to six carbon atoms, wherein any one of the carbon atoms issubstituted with a C3-C6 cycloalkoxy group as defined herein.

The term “heterocyclic” refers to a saturated, monovalent, monocyclicring having the indicated number of total ring atoms, in which at leastone of the ring atoms is a heteroatom (e.g., N or O).

The term “heterospirocyclic ring” as used herein refers to a bicyclic,saturated, spiro-C-fused (i.e., the two rings share a common carbonatom) heterocyclic ring system having from seven to ten total ringatoms, wherein from one to two of the ring atoms is a heteroatomindependently selected from the group consisting of N and O, providedthat the heteroatoms are not adjacent to one another. Each ringindependently contains from 3 to 7 ring atoms, and when two of the ringatoms are heteroatoms, each of the heteroatoms can be present in thesame ring, or each can be present in a different ring. Examples include7-oxa-4-azaspiro[2.5]octane, 2-azaspiro[3.3]heptane,2,6-diazaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane,2,6-diazaspiro[3.4]octane, 1,6-diazaspiro[3.4]octane,1,7-diazaspiro[4.4]nonane, 2,7-diazaspiro[4.4]nonane,2,7-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.5]nonane,2,5-diazaspiro[3.5]nonane, 1,7-diazaspiro[3.5]nonane,1,6-diazaspiro[3.5]nonane, 2,8-diazaspiro[4.5]decane,1,8-diazaspiro[4.5]decane, 1,7-diazaspiro[4.5]decane,2,7-diazaspiro[4.5]decane, 2,6-diazaspiro[4.5]decane,3,9-diazaspiro[5.5]undecane, 2,9-diazaspiro[5.5]undecane,7-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane,2-oxa-7-azaspiro[4.4]nonane, 7-oxa-2-azaspiro[3.5]nonane and7-oxa-2-azaspiro[4.5]decane. For purposes of clarification, the chemicalstructures of two exemplary heterospirocyclic rings are provided:

The term “(C3-C4)cycloalkyl” as used herein refers collectively to thecyclopropyl and cyclobutyl rings.

The term “heteroaryl” refers to an aromatic, monovalent or divalent,monocyclic or bicyclic ring having the indicated number of total ringatoms, in which at least one of the ring atoms is a heteroatom (e.g., Nor O).

The term “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopically enrichedvariants of the structures depicted. Compounds herein identified by nameor structure as one particular tautomeric form are intended to includeother tautomeric forms unless otherwise specified.

The term “tautomer” as used herein refers to compounds whose structuresdiffer markedly in arrangement of atoms, but which exist in easy andrapid equilibrium, and it is to be understood that compounds of thepresent invention may be depicted as different tautomers, and whencompounds have tautomeric forms, all tautomeric forms are intended to bewithin the scope of the invention, and the naming of the compounds doesnot exclude any tautomer.

In certain embodiments of Formula I, X is N.

In certain embodiments of Formula I, X is CH.

In certain embodiments of Formula I, Ring A is pyrazolyl optionallysubstituted with one to three R¹ groups, wherein each R¹ group isindependently selected from the group consisting of (a) hydrogen, (b)C1-C6 alkyl (optionally substituted with 1-3 fluoros), (c) hydroxy(C1-C6alkyl)- (optionally substituted with 1-3 fluoros), (d) dihydroxy(C1-C6alkyl)-(optionally substituted with 1-3 fluoros), (e) cyano(C1-C6alkyl)-, (f) R^(a)R^(b)N(C1-C6 alkyl)-, (g) (C1-C3 alkoxy)C1-C6 alkyl-(optionally substituted with 1-3 fluoros), (h) (C3-C6cycloalkyl)(CH₂)_(n)— where n is 0-3 and said cycloalkyl is optionallysubstituted with CN, OH, R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy, (i)hetCyc¹(CH₂)_(m)— where m is 0-3, (j) hetCyc²(CH₂)_(p)— where p is 0 or1, (k) hetAr¹(CH₂)_(q)— where q is 1 or 2, (1) halogen and (m)hetCyc¹C(═O)CH₂—. In certain embodiments, z is 1.

In certain embodiments of Formula I, Ring A is pyrazolyl optionallysubstituted with one to three R¹ groups, wherein each R¹ group isindependently selected from the group consisting of (a) hydrogen, (b)C1-C6 alkyl (optionally substituted with 1-3 fluoros), (c) hydroxy(C1-C6alkyl)- (optionally substituted with 1-3 fluoros), (e) cyano(C1-C6alkyl)-, (g) (C1-C3 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3fluoros), (h) (C3-C6 cycloalkyl)(CH₂)_(n)— where n is 0-3 and saidcycloalkyl is optionally substituted with CN, OH, R^(a)R^(b)N—,(1-3C)alkyl or (1-3C)alkoxy, (i) hetCyc¹(CH₂)_(m)— where m is 0-3, (j)hetCyc²(CH₂)_(p) where p is 0 or 1, (1) halogen and (m)hetCyc¹C(═O)CH₂—. In certain embodiments, z is 1.

In certain embodiments of Formula I, R¹ is hydrogen. In one embodimentof Formula I, R¹ is hydrogen and z is 1, 2 or 3.

In certain embodiments of Formula I, R¹ is C1-C6 alkyl optionallysubstituted with 1-3 fluoros. Non-limiting examples of R¹ includemethyl, isopropyl, isobutyl, pentan-3-yl, 2,2-difluoroethyl, and3,3,3-trifluoroethyl.

In certain embodiments of Formula I, R¹ is C1-C6 alkyl optionallysubstituted with 1-3 fluoros and z is 1, 2 or 3. In certain embodiments,z is 1. In certain embodiments of Formula I, Ring A is substituted withone to two R¹ groups independently selected from C1-C6 alkyl optionallysubstituted with 1-3 fluoros. In certain embodiments of Formula I, RingA is substituted with one or two methyl groups. In certain embodimentsof Formula I, Ring A is substituted with two or three groupsindependently selected from methyl and trifluoromethyl.

In certain embodiments of Formula I, R¹ is hydroxy(C1-C6 alkyl)-optionally substituted with 1-3 fluoros, and z is 1, 2 or 3. In certainembodiments of Formula I, R¹ is hydroxy(C3-C6 alkyl)- optionallysubstituted with 1-3 fluoros. In certain embodiments of Formula I, R¹ ishydroxy(C1-C6 alkyl) optionally substituted with 1-3 fluoros and z is 1.Non-limiting examples of R¹ include the structures:

In certain embodiments of Formula I, R¹ is dihydroxy(C1-C6 alkyl)-optionally substituted with 1-3 fluoros, and z is 1, 2 or 3. In certainembodiments of Formula I, R¹ is dihydroxy(C1-C6 alkyl)- optionallysubstituted with 1-3 fluoros and z is 1. In certain embodiments, R¹ isdihydroxy(C3-C6 alkyl)-. Non-limiting examples of R¹ include thestructures:

In certain embodiments of Formula I, R¹ is cyano(C1-C6 alkyl)-, and z is1, 2 or 3. In certain embodiments of Formula I, R¹ is cyano(C1-C6alkyl)- and z is 1. A non-limiting example of R¹ includes the structure:

In certain embodiments of Formula I, R¹ is R^(a)R^(b)N(C1-C6 alkyl)-,where R^(a) and R^(b) are independently hydrogen or C1-C6 alkyloptionally substituted with F, OH or C1-C6 alkoxy, and z is 1, 2 or 3.In certain embodiments of Formula I, R¹ is R^(a)R^(b)N(C1-C6 alkyl)- andz is 1. Non-limiting examples of R¹ include the structures:

In certain embodiments of Formula I, R¹ is (C1-C3 alkoxy)C1-C6 alkyl-optionally substituted with 1-3 fluoros, and z is 1, 2 or 3. In certainembodiments of Formula I, R¹ is (C1-C3 alkoxy)C1-C6 alkyl- optionallysubstituted with 1-3 fluoros and z is 1. Non-limiting examples of R¹include the structures:

In certain embodiments of Formula I, R¹ is (C3-C6 cycloalkyl)(CH₂)_(n)—where n is 0-3 and said cycloalkyl is optionally substituted with CN,OH, R^(a)R^(b)N—, (1-3C)alkyl, or (1-3C)alkoxy, and z is 1, 2 or 3. Incertain embodiments of Formula I, R¹ is (C3-C6 cycloalkyl)(CH₂)_(n)—where n is 0-3 and said cycloalkyl is optionally substituted with CN. Incertain embodiments, n is 0 or 1. In certain embodiments of Formula I,R¹ is (C3-C6 cycloalkyl)(CH₂)_(n)— and z is 1. Non-limiting examples ofR¹ include the structures:

In certain embodiments of Formula I, R¹ is hetCyc¹(CH₂)_(m)—, and z is1, 2 or 3, where m is 0-3, and hetCyc¹ is a 4-7 membered saturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O, wherein said heterocyclic ring is optionally substitutedwith one or more substituents independently selected from the groupconsisting of fluoro, HO, C1-C6 alkyl (optionally substituted with 1-3fluoros), (C1-C6 alkoxy)C1-C6 alkyl-(optionally substituted with 1-3fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-,R^(c)R^(d)N- and (C1-C6 alkyl)C(═O)—.

In certain embodiments of Formula I, R¹ is hetCyc¹(CH₂)_(m) and z is 1,2 or 3, where m is 0-3, and hetCyc¹ is azetidinyl, piperidinyl ormorpholinyl optionally substituted with one or more substituentsindependently selected from the group consisting of fluoro, HO, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl- (optionally substituted with 1-3 fluoros), (C3-C6cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl), R^(c)R^(d)N- and (C1-C6alkyl)C(═O)—.

In certain embodiments of Formula I, R¹ is hetCyc¹(CH₂)_(m)—, where m is0-3, and hetCyc¹ is azetidinyl, piperidinyl or morpholinyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of C1-C6 alkyl (optionally substituted with 1-3fluoros) and (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3fluoros). In certain embodiments, z is 1.

In certain embodiments of Formula I, R¹ is hetCyc¹(CH₂)_(m) and z is 1.In one embodiment, m is 0, 1 or 2. In one embodiment, m is 0. In oneembodiment, m is 1. In one embodiment, m is 2.

Non-limiting examples of R¹ when represented by hetCyc¹(CH₂)_(m)—include the structures:

In certain embodiments of Formula I, R¹ is hetCyc²(CH₂)_(p)— where p is0 or 1, and hetCyc² is a 7-10 membered heterospirocyclic ring having 1-2ring heteroatoms independently selected from N and O, wherein saidheterospirocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl- (optionally substituted with 1-3 fluoros), (C3-C6cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R^(c)R^(d)N- and (C1-C6alkyl)C(═O)—, and z is 1, 2 or 3.

In certain embodiments of Formula I, R¹ is hetCyc²(CH₂)_(p)— where p is0 or 1, and hetCyc² is a 7-10 membered heterospirocyclic ring having 1-2ring heteroatoms independently selected from N and O, wherein saidheterospirocyclic ring is unsubstituted.

In certain embodiments of Formula I, R¹ is hetCyc²(CH₂)_(p)— and z is 1.

Non-limiting examples when R¹ is represented by hetCyc²(CH₂)_(p)—include the structures:

In certain embodiments of Formula I, R¹ is hetAr¹(CH₂)_(q)— where q is 1or 2 and hetAr¹ is a 6-membered heteroaryl ring having 1-2 ring nitrogenatoms, wherein said ring is optionally substituted with one or moresubstituents independently selected from C1-C6 alkyl and halogen, and zis 1, 2 or 3.

In certain embodiments of Formula I, R¹ is hetAr¹(CH₂)_(q)— and z is 1.

Non-limiting examples when R¹ is represented by hetAr¹(CH₂)_(q)— includethe structures:

In certain embodiments of Formula I, R¹ is halogen. In certainembodiments when R¹ is halogen, z is 1, 2 or 3. Non-limiting examples ofR¹ include F, Cl and Br. In one embodiment of Formula I, R¹ is F and zis 1 or 2. In one embodiment, z is 1.

In certain embodiments of Formula I, R¹ is hetCyc¹C(═O)CH₂—, and z is 1,2 or 3, where m is 0-3, and hetCyc¹ is a 4-7 membered saturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O, wherein said heterocyclic ring is optionally substitutedwith one or more substituents independently selected from the groupconsisting of fluoro, HO, C1-C6 alkyl (optionally substituted with 1-3fluoros), (C1-C6 alkoxy)C1-C6 alkyl-(optionally substituted with 1-3fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-,R^(c)R^(d)N- and (C1-C6 alkyl)C(═O)—. In one embodiment, hetCyc¹ ispiperidinyl or morpholinyl optionally substituted with one or moresubstituents independently selected from the group consisting of fluoro,HO, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl), R^(c)R^(d)N- and (C1-C6alkyl)C(═O)—. In certain embodiments, hetCyc¹ is piperidinyl ormorpholinyl optionally substituted with one or more substituentsindependently selected from the group consisting of C1-C6 alkyl(optionally substituted with 1-3 fluoros) and (C1-C6 alkoxy)C1-C6 alkyl-(optionally substituted with 1-3 fluoros). In certain embodiments, zis 1. A non-limiting example of hetCyc¹C(═O)CH₂— is the structure:

In certain embodiments of Formula I, Ring A is pyrazolyl optionallysubstituted with one to three R¹ groups (that is, z is 1, 2 or 3),wherein R¹ is selected from the group consisting of (b) C1-C6 alkyl(optionally substituted with 1-3 fluoros), (c) hydroxy(C1-C6alkyl)-(optionally substituted with 1-3 fluoros), (e) cyano(C1-C6alkyl)-, (f) R^(a)R^(b)N(C1-C6 alkyl)-, (h) (C3-C6 cycloalkyl)(CH₂)_(n)—where n is 0-3 and said cycloalkyl is optionally substituted with CN,OH, R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy, (i) hetCyc¹(CH₂)_(m)—where m is 0-3, (j) hetCyc²(CH₂)_(p)— where p is 0 or 1, and (m)hetCyc¹C(═O)CH₂—. In certain embodiments, z is 1

In certain embodiments of Formula I, Ring A is pyrazolyl optionallysubstituted with two or three R¹ groups (that is, z is 2 or 3), whereineach R¹ is independently selected from hydrogen and C1-C6 alkyl(optionally substituted with 1-3 fluoros).

In certain embodiments of Formula I, z is 1 and Ring A is pyrazolyl,which may be represented by the structure:

wherein the wavy line indicates the point of attachment to the6-membered ring comprising X and the asterisk indicates the point ofattachment to R¹, wherein R¹ is selected from (a) hydrogen, (b) C1-C6alkyl (optionally substituted with 1-3 fluoros), (c) hydroxy(C1-C6alkyl)- (optionally substituted with 1-3 fluoros), (e) cyano(C1-C6alkyl), (g) (C1-C3 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3fluoros), (h) (C3-C6 cycloalkyl)(CH₂)_(n)— where n is 0-3 and saidcycloalkyl is optionally substituted with CN, OH, R^(a)R^(b)N—,(1-3C)alkyl or (1-3C)alkoxy, (i) hetCyc¹(CH₂)_(m)— where m is 0-3, (j)hetCyc²(CH₂)_(p) where p is 0 or 1, (1) halogen and (m)hetCyc¹C(═O)CH₂—. In one embodiment, R¹ is selected from (b) C1-C6 alkyl(optionally substituted with 1-3 fluoros), (c) hydroxy(C1-C6 alkyl)-(optionally substituted with 1-3 fluoros), (e) cyano(C1-C6 alkyl)-, (f)R^(a)R^(b)N(C1-C6 alkyl)-, (h) (C3-C6 cycloalkyl)(CH₂)_(n)— where n is0-3 and said cycloalkyl is optionally substituted with CN, OH,R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy, (i) hetCyc¹(CH₂)_(m)— where mis 0-3, (j) hetCyc²(CH₂)_(p)— where p is 0 or 1, and (m)hetCyc¹C(═O)CH₂—.

In certain embodiments of Formula I, Ring A is pyrazolyl and z is 1,wherein Ring A and R¹ together may be represented by the structure:

wherein the wavy line indicates the point of attachment to the6-membered ring comprising X, wherein z is 1 and R¹ is selected from (a)hydrogen, (b) C1-C6 alkyl (optionally substituted with 1-3 fluoros), (c)hydroxy(C1-C6 alkyl)- (optionally substituted with 1-3 fluoros), (e)cyano(C1-C6 alkyl)-, (g) (C1-C3 alkoxy)C1-C6 alkyl- (optionallysubstituted with 1-3 fluoros), (h) (C3-C6 cycloalkyl)(CH₂)_(n)— where nis 0-3 and said cycloalkyl is optionally substituted with CN, OH,R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy, (i) hetCyc¹(CH₂)_(m)— where mis 0-3, (j) hetCyc²(CH₂)_(p)— where p is 0 or 1, (1) halogen and (m)hetCyc¹C(═O)CH₂—. In one embodiment, R¹ is selected from (b) C1-C6 alkyl(optionally substituted with 1-3 fluoros), (c) hydroxy(C1-C6 alkyl)-(optionally substituted with 1-3 fluoros), (e) cyano(C1-C6 alkyl)-, (f)R^(a)R^(b)N(C1-C6 alkyl)-, (h) (C3-C6 cycloalkyl)(CH₂)_(n)— where n is0-3 and said cycloalkyl is optionally substituted with CN, OH,R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy, (i) hetCyc¹(CH₂)_(m)— where mis 0-3, and (m) hetCyc¹C(═O)CH₂—.

In certain embodiments of Formula I, R² is Ar¹, where Ar¹ is phenylsubstituted with one or more groups independently selected from halogen,cyano, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—, (C1-C3alkyl)C(═O)NH—, (cyclopropyl)C(═O)NH— and (cyclopropyl)NHC(═O)—, whereineach of said C1-C3 alkyl and C1-C3 alkoxy portions are optionallysubstituted with 1-3 fluoros.

In certain embodiments of Formula I, R² is Ar¹, where Ar¹ is phenylsubstituted with one or more groups independently selected from halogen,cyano, C1-C3 alkyl, C1-C3 alkoxy and (C1-C3 alkyl)NHC(═O)—, wherein eachof said C1-C3 alkyl and C1-C3 alkoxy portions is optionally substitutedwith 1-3 fluoros.

Non-limiting examples of R² when represented by Ar¹ include thestructures:

In certain embodiments of Formula I, R² is hetAr², where hetAr² is a6-10 membered heteroaryl ring having 1-2 ring nitrogen atoms, whereinsaid ring is optionally substituted with one or more groupsindependently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (C3-C4 cycloalkyl)C(═O)NH— and(C3-C4 cycloalkyl)NHC(═O)—, wherein each of said C1-C3 alkyl and C1-C3alkoxy portions is optionally substituted with 1-3 fluoros.

In certain embodiments of Formula I, R² is hetAr², where hetAr² is a6-10 membered heteroaryl ring having 1-2 ring nitrogen atoms, whereinsaid ring is optionally substituted with one or more groupsindependently selected from C1-C3 alkyl, C1-C3 alkoxy and (C1-C3alkyl)NHC(═O)—, wherein each of said C1-C3 alkyl and C1-C3 alkoxyportions is optionally substituted with 1-3 fluoros.

Non-limiting examples of hetAr² include:

In certain embodiments of Formula I, R³ is H.

In certain embodiments of Formula I, R³ is C1-C4 alkyl. Non-limitingexamples include methyl, ethyl, propyl, isopropyl and isobutyl.

In certain embodiments of Formula I, R³ is (C3-C4)cycloalkyl. In certainembodiments of Formula I, R³ is cyclopropyl. In certain embodiments ofFormula I, R³ is cyclobutyl.

Compounds of Formula I include compounds of Formula I-A, wherein:

X is N;

z is 1;

Ring A is

wherein the wavy line indicates the point of attachment to the6-membered ring comprising X and the asterisk indicates the point ofattachment to R¹;

each R¹ is independently selected from the group consisting of (a)hydrogen, (b) C1-C6 alkyl (optionally substituted with 1-3 fluoros), (c)hydroxy(C1-C6 alkyl)- (optionally substituted with 1-3 fluoros), (d)dihydroxy(C1-C6 alkyl)- (optionally substituted with 1-3 fluoros), (e)cyano(C1-C6 alkyl)-, (f) R^(a)R^(b)N(C1-C6 alkyl)-, (g) (C1-C3alkoxy)C1-C6 alkyl-(optionally substituted with 1-3 fluoros), (h) (C3-C6cycloalkyl)(CH₂)_(n)— where n is 0-3 and said cycloalkyl is optionallysubstituted with CN, OH, R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy, (i)hetCyc¹(CH₂)_(m)— where m is 0-3, (j) hetCyc²(CH₂)_(p)— where p is 0 or1, (k) hetAr¹(CH₂)_(q)— where q is 1 or 2, (l) halogen and (m)hetCyc¹C(═O)CH₂—;

hetCyc¹ is a 4-7 membered saturated heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of fluoro,HO, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R^(c)R^(d)N- and (C1-C6alkyl)C(═O)—;

hetCyc² is a 7-10 membered heterospirocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterospirocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl- (optionally substituted with 1-3 fluoros), (C3-C6cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R^(c)R^(d)N- and (C1-C6alkyl)C(═O)—;

hetAr¹ is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms,wherein said ring is optionally substituted with one or moresubstituents independently selected from C1-C6 alkyl and halogen;

R² is Ar¹ or hetAr²;

Ar¹ is phenyl substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—,(C1-C3 alkyl)C(═O)NH—, (cyclopropyl)C(═O)NH— and (cyclopropyl)NHC(═O)—,wherein each of said C1-C3 alkyl and C1-C3 alkoxy portions is optionallysubstituted with 1-3 fluoros;

hetAr² is a 6-10 membered heteroaryl ring having 1-2 ring nitrogenatoms, wherein said heteroaryl ring is optionally substituted with oneor more groups independently selected from halogen, C1-C3 alkyl, C1-C3alkoxy, (C1-C3 alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (C3-C4cycloalkyl)C(═O)NH— and (C3-C4 cycloalkyl)NHC(═O)—, wherein each of saidC1-C3 alkyl and C1-C3 alkoxy portions is optionally substituted with 1-3fluoros;

R³ is hydrogen, C1-C4 alkyl or (C3-C4)cycloalkyl; and

R^(a), R^(b), R^(c) and R^(d) are independently hydrogen or C1-C6 alkyloptionally substituted with F, OH or C1-C6 alkoxy.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is as definedfor Formula I-A.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—.

In one embodiment of Formula I-A, R³ is hydrogen.

In one embodiment of Formula I-A, R³ is C1-C4 alkyl.

In one embodiment of Formula I-A, R³ is (C3-C4)cycloalkyl.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—, and R³ is hydrogen.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—, and R³ is C1-C4 alkyl.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—, and R³ is (C3-C4)cycloalkyl.

In one embodiment of Formula I-A, R¹ is selected from (b) C1-C6 alkyl(optionally substituted with 1-3 fluoros), (c) hydroxy(C1-C6 alkyl)-(optionally substituted with 1-3 fluoros), (e) cyano(C1-C6 alkyl)-, (f)R^(a)R^(b)N(C1-C6 alkyl)-, (h) (C3-C6 cycloalkyl)(CH₂)_(n)— where n is0-3 and said cycloalkyl is optionally substituted with CN, OH,R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy, (i) hetCyc¹(CH₂)_(m)— where mis 0-3, (j) hetCyc²(CH₂)_(p)— where p is 0 or 1, and (m)hetCyc¹C(═O)CH₂—; and hetCyc¹, R^(a), and R^(b) are as defined forFormula I-A.

In one embodiment of Formula I-A, R¹ is C1-C6 alkyl (optionallysubstituted with 1-3 fluoros).

In one embodiment of Formula I-A, R¹ is hydroxy(C1-C6 alkyl)-(optionally substituted with 1-3 fluoros).

In one embodiment of Formula I-A, R¹ is cyano(C1-C6 alkyl)-.

In one embodiment of Formula I-A, R¹ is R^(a)R^(b)N(C1-C6 alkyl)-.

In one embodiment of Formula I-A, R¹ is (C3-C6 cycloalkyl)(CH₂)_(n)—where n is 0-3 and said cycloalkyl is optionally substituted with CN,OH, R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy,

In one embodiment of Formula I-A, R¹ is hetCyc¹(CH₂)_(m)— where m is0-3. In one embodiment, m is 0, 1 or 2. In one embodiment, m is 0. Inone embodiment, m is 1. In one embodiment, m is 2.

In one embodiment of Formula I-A, R¹ is hetCyc²(CH₂)_(p)— where p is 0or 1.

In one embodiment of Formula I-A, R¹ is hetCyc¹C(═O)CH₂—.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is hydrogen; R¹ is selected from (b) C1-C6alkyl (optionally substituted with 1-3 fluoros), (c) hydroxy(C1-C6alkyl)- (optionally substituted with 1-3 fluoros), (e) cyano(C1-C6alkyl)-, (f) R^(a)R^(b)N(C1-C6 alkyl)-, (h) (C3-C6 cycloalkyl)(CH₂)_(n)—where n is 0-3 and said cycloalkyl is optionally substituted with CN,OH, R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy, (i) hetCyc¹(CH₂)_(m)—where m is 0-3, (j) hetCyc²(CH₂)_(p)— where p is 0 or 1, and (m)hetCyc¹C(═O)CH₂—; and hetCyc¹, R^(a), and R^(b) are as defined forFormula I-A. In one embodiment, m is 0, 1 or 2. In one embodiment, m is0. In one embodiment, m is 1. In one embodiment, m is 2.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is C1-C4 alkyl; R¹ is selected from (b) C1-C6alkyl (optionally substituted with 1-3 fluoros), (c) hydroxy(C1-C6alkyl)- (optionally substituted with 1-3 fluoros), (e) cyano(C1-C6alkyl)-, (f) R^(a)R^(b)N(C1-C6 alkyl)-, (h) (C3-C6 cycloalkyl)(CH₂)_(n)—where n is 0-3 and said cycloalkyl is optionally substituted with CN,OH, R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy, (i) hetCyc¹(CH₂)_(m)—where m is 0-3, (j) hetCyc²(CH₂)_(p)— where p is 0 or 1, and (m)hetCyc¹C(═O)CH₂—; and hetCyc¹, R^(a), and R^(b) are as defined forFormula I-A. In one embodiment, m is 0, 1 or 2. In one embodiment, m is0. In one embodiment, m is 1. In one embodiment, m is 2.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is (C3-C4)cycloalkyl; R¹ is selected from (b)C1-C6 alkyl (optionally substituted with 1-3 fluoros), (c) hydroxy(C1-C6alkyl)- (optionally substituted with 1-3 fluoros), (e) cyano(C1-C6alkyl)-, (f) R^(a)R^(b)N(C1-C6 alkyl)-, (h) (C3-C6 cycloalkyl)(CH₂)_(n)—where n is 0-3 and said cycloalkyl is optionally substituted with CN,OH, R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy, (i) hetCyc¹(CH₂)_(m)—where m is 0-3, (j) hetCyc²(CH₂)_(p)— where p is 0 or 1, and (m)hetCyc¹C(═O)CH₂—; and hetCyc¹, R^(a), and R^(b) are as defined forFormula I-A. In one embodiment, m is 0, 1 or 2. In one embodiment, m is0. In one embodiment, m is 1. In one embodiment, m is 2.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is hydrogen; and R¹ is C1-C6 alkyl (optionallysubstituted with 1-3 fluoros).

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, C1-C3 alkyl (optionally substituted with 1-3 fluoros), andC1-C3 alkoxy (optionally substituted with 1-3 fluoros); R³ is hydrogen;and R¹ is hydroxy(C1-C6 alkyl)- (optionally substituted with 1-3fluoros).

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, C1-C3 alkyl (optionally substituted with 1-3 fluoros), andC1-C3 alkoxy (optionally substituted with 1-3 fluoros); R³ is hydrogen;and R¹ is cyano(C1-C6 alkyl)-.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is hydrogen; and R¹ is R^(a)R^(b)N(C1-C6alkyl)- where R^(a), and R^(b) are as defined for Formula I-A.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is hydrogen; and R¹ is (C3-C6cycloalkyl)(CH₂)_(n)— where n is 0-3 and said cycloalkyl is optionallysubstituted with CN, OH, R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy. Inone embodiment said cycloalkyl is unsubstituted. In one embodiment, saidcycloalkyl is substituted with CN. In one embodiment, n is 0. In oneembodiment n is 1.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is hydrogen; R¹ is hetCyc¹(CH₂)_(m)— where mis 0-3; and hetCyc¹ is as defined for Formula I-A. In one embodiment, mis 0, 1 or 2. In one embodiment, m is 0. In one embodiment, m is 1. Inone embodiment, m is 2.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is hydrogen; and R¹ is hetCyc²(CH₂)_(p)— wherep is 0 or 1, and hetCyc² is as defined for Formula I-A. In oneembodiment, p is 1. On one embodiment, hetCyc²(CH₂)_(p)— is

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is hydrogen; and R¹ is hetCyc¹C(═O)CH₂— wherehetCyc¹ is as defined for Formula I-A. In one embodiment, hetCyc¹ ispiperidinyl. In one embodiment, hetCyc¹C(═O)CH₂— is

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is C1-C4 alkyl; and R¹ is C1-C6 alkyl(optionally substituted with 1-3 fluoros).

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is C1-C4 alkyl; and R¹ is R^(a)R^(b)N(C1-C6alkyl)-, wherein R^(a) and R^(b) are as defined for Formula I-A. In oneembodiment, R^(a) and R^(b) are independently selected from C1-C6 alkyl.

In one embodiment of Formula I-A, R² is Ar¹, where Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is C1-C4 alkyl; and R¹ is hetCyc¹(CH₂)_(m)—where m is 0-3, and hetCyc¹ is as defined for Formula I-A.

In one embodiment of Formula I-A, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl (optionally substituted with 1-3fluoros), C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is C3-C4 cycloalkyl; and R¹ is C1-C6 alkyl(optionally substituted with 1-3 fluoros).

Compounds of Formula I include compounds of Formula I-B, wherein:

X is N;

z is 2 or 3;

Ring A is pyrazolyl;

each R¹ is independently selected from the group consisting of (a)hydrogen and (b) C1-C6 alkyl (optionally substituted with 1-3 fluoros);

R² is Ar¹;

Ar¹ is phenyl substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—,(C1-C3 alkyl)C(═O)NH—, (cyclopropyl)C(═O)NH— and (cyclopropyl)NHC(═O)—,wherein each of said C1-C3 alkyl and C1-C3 alkoxy portions is optionallysubstituted with 1-3 fluoros; and

R³ is hydrogen, C1-C4 alkyl or (C3-C4)cycloalkyl.

In one embodiment of Formula I-B, Ar¹ is phenyl substituted with one ormore groups independently selected from halogen and C1-C3 alkoxy.

In one embodiment of Formula I-B, R³ is hydrogen.

In one embodiment of Formula I-B, Ar¹ is phenyl substituted with one ormore groups independently selected from halogen and C1-C3 alkoxy, and R³is hydrogen.

Compounds of Formula I include compounds of Formula I-C, wherein:

X is CH;

z is 1;

Ring A is

wherein the wavy line indicates the point of attachment to the6-membered ring comprising X and the asterisk indicates the point ofattachment to R¹;

R¹ is selected from the group consisting of (a) hydrogen, (b) C1-C6alkyl (optionally substituted with 1-3 fluoros), (c) hydroxy(C1-C6alkyl)- (optionally substituted with 1-3 fluoros), (d) dihydroxy(C1-C6alkyl)- (optionally substituted with 1-3 fluoros), (e) cyano(C1-C6alkyl)-, (f) R^(a)R^(b)N(C1-C6 alkyl)-, (g) (C1-C3 alkoxy)C1-C6 alkyl-(optionally substituted with 1-3 fluoros), (h) (C3-C6cycloalkyl)(CH₂)_(n)— where n is 0-3 and said cycloalkyl is optionallysubstituted with CN, OH, R^(a)R^(b)N—, (1-3C)alkyl or (1-3C)alkoxy, (i)hetCyc¹(CH₂)_(m)— where m is 0-3, (j) hetCyc²(CH₂)_(p)— where p is 0 or1, (k) hetAr¹(CH₂)_(q)— where q is 1 or 2, (1) halogen and (m)hetCyc¹C(═O)CH₂—;

hetCyc¹ is a 4-7 membered saturated heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of fluoro,HO, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R^(c)R^(d)N- and (C1-C6alkyl)C(═O)—;

hetCyc² is a 7-10 membered heterospirocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterospirocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl- (optionally substituted with 1-3 fluoros), (C3-C6cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R^(c)R^(d)N- and (C1-C6alkyl)C(═O)—;

hetAr¹ is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms,wherein said ring is optionally substituted with one or moresubstituents independently selected from C1-C6 alkyl and halogen;

R² is Ar¹ or hetAr²;

Ar¹ is phenyl substituted with one or more groups independently selectedfrom halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—,(C1-C3 alkyl)C(═O)NH—, (cyclopropyl)C(═O)NH— and (cyclopropyl)NHC(═O)—,wherein each of said C1-C3 alkyl and C1-C3 alkoxy portions is optionallysubstituted with 1-3 fluoros;

hetAr² is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms,wherein said heteroaryl ring is optionally substituted with one or moregroups independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy,(C1-C3 alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (C3-C4 cycloalkyl)C(═O)NH—and (C3-C4 cycloalkyl)NHC(═O)—, wherein each of said C1-C3 alkyl andC1-C3 alkoxy portions is optionally substituted with 1-3 fluoros;

R³ is hydrogen, C1-C4 alkyl or (C3-C4)cycloalkyl; and

R^(a), R^(b), R^(c) and R^(d) are independently hydrogen or C1-C6 alkyloptionally substituted with F, OH or C1-C6 alkoxy.

In one embodiment of Formula I-C, R² is Ar¹, wherein Ar¹ is as definedfor Formula I-B.

In one embodiment of Formula I-C, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, C1-C3 alkyl (optionally substituted with 1-3 fluoros), andC1-C3 alkoxy (optionally substituted with 1-3 fluoros).

In one embodiment of Formula I-C, R³ is hydrogen.

In one embodiment of Formula I-C, R³ is C1-C4 alkyl.

In one embodiment of Formula I-C, R³ is (C3-C4)cycloalkyl.

In one embodiment of Formula I-C, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; and R³ is hydrogen.

In one embodiment of Formula I-C, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; and R³ is C1-C4 alkyl.

In one embodiment of Formula I-C, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; and R³ is (C3-C4)cycloalkyl.

In one embodiment of Formula I-C, R¹ is independently selected from (b)C1-C6 alkyl (optionally substituted with 1-3 fluoros) and (i)hetCyc¹(CH₂)_(m)— where m is 0-3; and hetCyc¹ is defined for FormulaI-C.

In one embodiment of Formula I-C, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is hydrogen; R¹ is independently selected from(b) C1-C6 alkyl (optionally substituted with 1-3 fluoros) and (i)hetCyc¹(CH₂)_(m)— where m is 0-3; and hetCyc¹ is defined for FormulaI-C.

In one embodiment of Formula I-C, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is C1-C4 alkyl; R¹ is independently selectedfrom (b) C1-C6 alkyl (optionally substituted with 1-3 fluoros) and (i)hetCyc¹(CH₂)_(m)— where m is 0-3; and hetCyc¹ is defined for FormulaI-C.

In one embodiment of Formula I-C, R² is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more groups independently selectedfrom halogen, C1-C3 alkoxy (optionally substituted with 1-3 fluoros) and(C1-C3 alkyl)NHC(═O)—; R³ is (C3-C4)cycloalkyl; R¹ is independentlyselected from (b) C1-C6 alkyl (optionally substituted with 1-3 fluoros)and (i) hetCyc¹(CH₂)_(m)— where m is 0-3; and hetCyc¹ is defined forFormula I-C.

It will be appreciated that certain compounds provided herein maycontain one or more centers of asymmetry and may therefore be preparedand isolated in a mixture of isomers such as a racemic mixture, or in anenantiomerically pure form.

It will further be appreciated that the compounds of Formula I or theirsalts may be isolated in the form of solvates, and accordingly that anysuch solvate is included within the scope of the present invention. Forexample, compounds of Formula I and salts thereof can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like.

The compounds of Formula I include pharmaceutically acceptable saltsthereof. In addition, the compounds of Formula I also include othersalts of such compounds which are not necessarily pharmaceuticallyacceptable salts, and which may be useful as intermediates for preparingand/or purifying compounds of Formula I and/or for separatingenantiomers of compounds of Formula I. Non-limiting examples of saltsinclude monochloride, dichloride, trifluoroacetic acid, anddi-trifluoroacetic acid salts of compounds of Formula I.

In one embodiment, the compounds of Formula I include the compounds ofExamples 1-62 and stereoisomers and pharmaceutically acceptable saltsand solvates thereof. In one embodiment, the compounds of Examples 1-83are in the free base form. In one embodiment, the compounds of Examples1-83 are monochloride, dichloride, trifluoroacetic acid, ordi-trifluoroacetic acid salts.

The term “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically, with theother ingredients comprising a formulation, and/or the patient beingtreated therewith.

Compounds provided herein may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. That is, an atom, in particular when mentioned in relation toa compound according to Formula I, comprises all isotopes and isotopicmixtures of that atom, either naturally occurring or syntheticallyproduced, either with natural abundance or in an isotopically enrichedform. For example, when hydrogen is mentioned, it is understood to referto ¹H, ²H, ³H or mixtures thereof; when carbon is mentioned, it isunderstood to refer to ¹¹C, ¹²C, ¹³C ¹⁴C or mixtures thereof; whennitrogen is mentioned, it is understood to refer to ¹³N, ¹⁴N, ¹⁵N ormixtures thereof; when oxygen is mentioned, it is understood to refer to¹⁴O, ¹⁵O, ¹⁶O, ¹⁷O, ¹⁸O or mixtures thereof; and when fluoro ismentioned, it is understood to refer to ¹⁸F, ¹⁹F or mixtures thereof.The compounds provided herein therefore also comprise compounds with oneor more isotopes of one or more atom, and mixtures thereof, includingradioactive compounds, wherein one or more non-radioactive atoms hasbeen replaced by one of its radioactive enriched isotopes. Radiolabeledcompounds are useful as therapeutic agents, e.g., cancer therapeuticagents, research reagents, e.g., assay reagents, and diagnostic agents,e.g., in vivo imaging agents. All isotopic variations of the compoundsprovided herein, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

For illustrative purposes, Schemes 1 and 1A show general methods forpreparing the compounds provided herein as well as key intermediates.For a more detailed description of the individual reaction steps, seethe Examples section below. Those skilled in the art will appreciatethat other synthetic routes may be used to synthesize the inventivecompounds. Although specific starting materials and reagents aredepicted in the Schemes and discussed below, other starting materialsand reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Scheme 1 shows a general scheme for the synthesis of compound 9 where X,R¹, R², R³, Ring A and z are as defined for Formula I. Compound 3, whereR³ is as defined for Formula I, may be obtained by treating compound 1(commercially available or prepared according to Scheme 2) with boronicacid 2, where R² is as defined for Formula I, in the presence of Cu(II)catalyst such as cupric acetate and a ligand such as pyridine. Compound3 may be reacted with a dioxoborinane, such as bis(pinacolato)diboron,using appropriate Suzuki coupling reaction conditions (e.g., in thepresence of a palladium (II) catalyst such as Pd(OAc)₂, Pd₂(dba)₃,Pd(PPh₃)₄ or Pd(Dppf)₂ and optionally in the presence of a suitableligand such as XPhos and in the presence of an inorganic base such aspotassium acetate or sodium carbonate), to provide compound 4 where R²and R³ are as defined for Formula I. Compound 4 may be reacted withcompound 5 (prepared as described below) where X, Ring A, R¹ and z areas defined for Formula I, using appropriate Suzuki coupling reactionconditions (e.g., in the presence of a palladium (II) catalyst such asPd(PPh₃)₄, Pd(Dppf)₂, Pd(OAc)₂, or Pd₂(dba)₃, and an inorganic base suchas potassium carbonate or sodium carbonate) to provide compound 9.Compound 5 may be prepared by reacting compound 6 (where R¹, Ring A andz are as defined for Formula I) with compound 7 (where X is as definedfor Formula I) to provide compound 8, which may subsequently bebrominated using standard conditions to provide compound 5. Thesyntheses of intermediates 3 and 6 which are not commercially availableare described in the Examples.

Scheme 1A shows a general scheme for the synthesis of compound 9B whereX, R² and R³ are as defined for Formula I, z is 1 and R¹ is a piperidinesubstituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros),(C1-C3 alkoxy)C1-C6 alkyl (optionally substituted with 1-3 fluoros) orhydroxy(C1-C6 alkyl). Compound 9A, where X, R² and R³ are as defined forFormula I, z is 1 and R¹ is a piperidine substituted with C1-C6 alkyl(optionally substituted with 1-3 fluoros), (C1-C3 alkoxy)C1-C6 alkyl(optionally substituted with 1-3 fluoros) or hydroxy(C1-C6 alkyl),prepared as described in Scheme 1, may be reacted with a compound havingthe formula R^(x)—Y, where R^(x) is C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C3 alkoxy)C1-C6 alkyl (optionally substitutedwith 1-3 fluoros) or hydroxy(C1-C6 alkyl), and Y is a leaving group suchas a halogen or a tosylate, under standard alkylation reactionconditions, for example in the presence of an inorganic base such aspotassium carbonate, to provide compound 9B.

The compound of formulas 1, 3, 4, 5, 6, 8 and 9A as shown and describedabove for Schemes 1 and 1A are useful as intermediates for preparingcompounds of Formula I and are provided as further aspects of theinvention.

Further provided herein is a process for preparing of a compound ofFormula I or a pharmaceutically acceptable salt thereof as definedherein which comprises:

(a) reacting a compound having the formula 5:

where X, Ring A, R¹ and z are as defined for Formula I, with a compoundhaving the formula 4:

where R² is as defined for Formula I, in the presence of a palladium(II) catalyst and an inorganic base; or

(b) for a compound of Formula I where X, R² and R³ are as defined forFormula I, z is 1 and R¹ is a piperidine substituted with C1-C6 alkyl(optionally substituted with 1-3 fluoros), (C1-C3 alkoxy)C1-C6 alkyl(optionally substituted with 1-3 fluoros) or hydroxy(C1-C6 alkyl),reacting a compound having the formula 9A:

where X, R² and Ring A are as defined for Formula I, with a compoundhaving the formula R^(x)—Y, where R^(x) is C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (C1-C3 alkoxy)C1-C6 alkyl (optionallysubstituted with 1-3 fluoros) or hydroxy(C1-C6 alkyl), and Y is aleaving group such as a halogen or a tosylate, under standard alkylationreaction conditions; and

removing any protecting groups if present and optionally forming apharmaceutically acceptable salt.

The ability of test compounds to act as inhibitors of FGFR1, FGFR2and/or FGFR3 may be demonstrated by the assay described in Example A.IC₅₀s are shown in Table F.

Compounds of Formula I have been found to inhibit FGFR1, FGFR2 and/orFGFR3, and are therefore believed to be useful for treating diseases anddisorders which can be treated with an inhibitor of FGFR1, FGFR2, FGFR3and/or FGFR4, such as FGFR-associated diseases and disorders, e.g.,proliferative disorders such as cancers, including hematological cancersand solid tumors.

In certain embodiments, compounds of Formula I are useful for preventingdiseases and disorders as defined herein (for example cancer).

The term “preventing” as used herein means the prevention of therecurrence or spread, in whole or in part, of the disease or conditionas described herein, or a symptom thereof.

As used herein, the word “a” before a noun represents one or more of theparticular noun. For example, the phrase “a cell” represents “one ormore cells.”

As used herein, terms “treat” or “treatment” refer to therapeutic orpalliative measures. Beneficial or desired clinical results include, butare not limited to, alleviation, in whole or in part, of symptomsassociated with a disease or disorder or condition, diminishment of theextent of disease, stabilized (i.e., not worsening) state of disease,delay or slowing of disease progression, amelioration or palliation ofthe disease state (e.g., one or more symptoms of the disease), andremission (whether partial or total). “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment.

The term “FGFR-associated disease or disorder” as used herein refers todiseases or disorders associated with or having a dysregulation of aFGFR gene, a FGFR protein, or the expression or activity, or level ofthe same (e.g., one or more of the same) (e.g., any of the types ofdysregulation of an FGFR gene, a FGFR protein, or expression oractivity, or level of the same, described herein). A non-limitingexample of an FGFR-associated disease or disorder is an FGFR-associatedcancer.

As used herein, the term “FGFR-associated cancer” shall be defined toinclude cancers associated with or having dysregulation of a FGFR gene,a FGFR protein, or expression or activity, or level of the same (e.g.,any of types of dysregulation of a FGFR gene, a FGFR protein, orexpression or activity, or level of the same, described herein).Non-limiting examples of a FGFR-associated cancer are described herein.

As used herein, the term “subject,” “individual,” or “patient,” usedinterchangeably, refers to any animal, including mammals such as mice,rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses,primates, and humans. In some embodiments, the patient is a human. Insome embodiments, the subject has experienced and/or exhibited at leastone symptom of the disease or disorder to be treated and/or prevented.In some embodiments, the subject has been identified or diagnosed ashaving a cancer with dysregulation of a FGFR gene, a FGFR protein, orexpression or activity, or level of the same (a FGFR-associated cancer)(e.g., as determined using a regulatory agency-approved, e.g.,FDA-approved, assay or kit). In some embodiments, the subject has atumor that is positive for dysregulation of a FGFR gene, a FGFR protein,or expression or activity, or level of the same (e.g., as determinedusing a regulatory agency-approved assay or kit). The subject can be asubject with a tumor(s) that is positive for dysregulation of a FGFRgene, a FGFR protein, or expression or activity, or level of the same(e.g., identified as positive using a regulatory agency-approved, e.g.,FDA-approved, assay or kit). The subject can be a subject whose tumorshave dysregulation of a FGFR gene, a FGFR protein, or expression oractivity, or a level of the same (e.g., where the tumor is identified assuch using a regulatory agency-approved, e.g., FDA-approved, kit orassay). In some embodiments, the subject is suspected of having aFGFR-associated cancer. In some embodiments, the subject has a clinicalrecord indicating that the subject has a tumor that has dysregulation ofa FGFR gene, a FGFR protein, or expression or activity, or level of thesame (and optionally the clinical record indicates that the subjectshould be treated with any of the compositions provided herein).

The term “FGFR” or “FGFR protein” includes any of the FGFR proteinsdescribed herein (e.g., a FGFR1, a FGFR2, a FGFR3 or a FGFR4 protein, orisoforms thereof).

The term “FGFR gene” includes any of the FGFR genes described herein(e.g., a FGFR1, a FGFR2, a FGFR3 gene, or a FGFR4 gene).

The term “wildtype” or “wild-type” describes a nucleic acid (e.g., aFGFR gene or a FGFR mRNA) or protein (e.g., a FGFR protein) that isfound in a subject that does not have a FGFR-associated disease, e.g., aFGFR-associated cancer (and optionally also does not have an increasedrisk of developing a FGFR-associated disease and/or is not suspected ofhaving a FGFR-associated disease), or is found in a cell or tissue froma subject that does not have a FGFR-associated disease, e.g., aFGFR-associated cancer (and optionally also does not have an increasedrisk of developing a FGFR-associated disease and/or is not suspected ofhaving a FGFR-associated disease).

The term “regulatory agency” is a country's agency for the approval ofthe medical use of pharmaceutical agents with the country. For example,a non-limiting example of a regulatory agency is the U.S. Food and DrugAdministration (FDA).

The phrase “dysregulation of a FGFR gene, a FGFR protein, or expressionor activity, or level of the same” is a genetic mutation (e.g., a FGFRgene translocation that results in the expression of a fusion protein, adeletion in a FGFR gene that results in the expression of a FGFR proteinthat includes a deletion of at least one amino acid as compared to thewild-type FGFR protein, or a mutation in a FGFR gene that results in theexpression of a FGFR protein with one or more point mutations, analternative spliced version of a FGFR mRNA that results in a FGFRprotein that results in the deletion of at least one amino acid in theFGFR protein as compared to the wild-type FGFR protein), or a FGFR geneamplification that results in overexpression of a FGFR protein) or anautocrine activity resulting from the overexpression of a FGFR gene acell, that results in a pathogenic increase in the activity of a kinasedomain of a FGFR protein (e.g., a constitutively active kinase domain ofa FGFR protein) in a cell. For example, a dysregulation of a FGFR gene,a FGFR protein, or expression or activity, or level of the same, can bea mutation in a FGFR1, FGFR2, FGFR3, or FGFR4 gene that encodes a FGFRprotein that is constitutively active or has increased activity ascompared to a protein encoded by a FGFR1, FGFR2, FGFR3, or FGFR4 genethat does not include the mutation. For example, a dysregulation of aFGFR gene, a FGFR protein, or expression or activity, or level of thesame, can be the result of a gene or chromosome translocation whichresults in the expression of a fusion protein that contains a firstportion of FGFR1, FGFR2, FGFR3, or FGFR4 that includes a functionalkinase domain, and a second portion of a partner protein (i.e., that isnot FGFR1, FGFR2, FGFR3, or FGFR4). In some examples, dysregulation of aFGFR gene, a FGFR protein, or expression or activity, can be a result ofa gene translation of one FGFR1 gene with another FGFR1 gene.Non-limiting examples of fusion proteins that are a result of a FGFRgene translocation are described in Table 3.

A dysregulation of a FGFR gene, a FGFR protein, or expression oractivity, or level of the same, can, e.g., include a mutation(s) in aFGFR1, FGFR2, FGFR3, or FGFR4 gene that results in a FGFR1, FGFR2,FGFR3, or FGFR4 protein containing at least one (e.g., two, three, four,or five) point mutations (e.g., one of more of the point mutationslisted in Table 1).

A dysregulation of a FGFR gene, a FGFR protein, or expression oractivity, or level of the same, can be a mutation in a FGFR1, FGFR2,FGFR3, or FGFR4 gene that results in a deletion of one or morecontiguous amino acids (e.g., at least two, at least three, at leastfour, at least 5, at least 6, at least 7, at least 8, at least 9, atleast 10, at least 15, at least 20, at least 30, at least 40, at least50, at least 60, at least 70, at least 80, at least 90, at least 100, atleast 110, at least 120, at least 130, at least 140, at least 150, atleast 160, at least 170, at least 180, at least 190, at least 200, atleast 210, at least 220, at least 230, at least 240, at least 250, atleast 260, at least 270, at least 280, at least 290, at least 300, atleast 310, at least 320, at least 330, at least 340, at least 350, atleast 360, at least 370, at least 380, at least 390, or at least 400amino acids) in the FGFR1, FGFR2, FGFR3, or FGFR4 protein (except forthe deletion of amino acids in the kinase domain of FGFR1, FGFR2, FGFR3,or FGFR4 that would result in inactivation of the kinase domain).

In some examples, a dysregulation of a FGFR gene, a FGFR protein, orexpression or activity, or level of the same, can include an alternatespliced form of a FGFR mRNA. In some examples, a dysregulation of a FGFRgene, a FGFR protein, or expression or activity, or level of the same,includes an amplification of a FGFR gene (e.g., one, two, three, or fouradditional copies of a FGFR1, FGFR2, FGFR3, and/or FGFR4 gene) that canresult, e.g., in an autocrine expression of a FGFR gene in a cell.

The term “mammal” as used herein, refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

The phrase “time of survival” means the length of time between theidentification or diagnosis of cancer (e.g., any of the cancersdescribed herein) in a subject or patient by a medical professional andthe time of death of the subject or patient (caused by the cancer).Methods of increasing the time of survival in a subject or patienthaving a cancer are described herein.

The term “metastasis” is an art known term and means the formation of anadditional tumor (e.g., a solid tumor) at a site distant from a primarytumor in a subject or patient, where the additional tumor includes thesame or similar cancer cells as the primary tumor.

The phrase “risk of developing a metastasis” means the risk that asubject or patient having a primary tumor will develop an additionaltumor (e.g., a solid tumor) at a site distant from a primary tumor in asubject or patient over a set period of time, where the additional tumorincludes the same or similar cancer cells as the primary tumor. Methodsfor reducing the risk of developing a metastasis in a subject or patienthaving a cancer are described herein.

The phrase “risk of developing additional metastases” means the riskthat a subject or patient having a primary tumor and one or moreadditional tumors at sites distant from the primary tumor (where the oneor more additional tumors include the same or similar cancer cells asthe primary tumor) will develop one or more further tumors distant fromthe primary tumor, where the further tumors include the same or similarcancer cells as the primary tumor. Methods for reducing the risk ofdeveloping additional metastasis are described herein.

The term “angiogenesis-related disorder” means a disease characterizedin part by an increased number or size of blood vessels in a tissue in asubject or patient, as compared to a similar tissue from a subject nothaving the disease. Non-limiting examples of angiogenesis-relateddisorders include: cancer (e.g., any of the exemplary cancers describedherein, such as prostate cancer, lung cancer, breast cancer, bladdercancer, renal cancer, colon cancer, gastric cancer, pancreatic cancer,ovarian cancer, melanoma, hepatoma, sarcoma, and lymphoma), exudativemacular degeneration, proliferative diabetic diabetic retinopathy,ischemic retinopathy, retinopathy of prematurity, neovascular glaucoma,iritis rubeosis, corneal neovascularization, cyclitis, sickle cellretinopathy, and pterygium.

The term “resistant cancer cell to an anti-cancer drug” means a cancercell that demonstrates an increased rate of growth and/or proliferationin the presence of an anti-cancer drug as compared to the rate of growthand/or proliferation of a similar cancer cell (or an average rate ofgrowth and/or proliferation of a population of a similar cancer cells).For example, a cancer cell that demonstrates an increased rate of growthand/or proliferation in the presence of an anti-cancer drug (as comparedto the rate of growth and/or proliferation of a similar cancer cell) canbe present in a patient or a subject (e.g., a patient or a subjecthaving a FGFR-associated cancer).

The term “increasing sensitivity to an anti-cancer drug” means adecrease in the rate of growth and/or proliferation of a resistantcancer cell (to an anti-cancer drug) when contacted with the anti-cancerdrug and at least one of the compounds described herein, as compared tothe rate of growth and/or proliferation of a resistant cancer cell whencontacted with the anti-cancer drug alone.

The FGFR receptors (FGFR1, FGFR2, FGFR3, and FGFR4) share severalstructural features in common, including three extracellularimmunoglobulin-like (Ig) domains, a hydrophobic transmembrane domain,and an intracellular split tyrosine kinase domain with a 14-amino acidinsertion (Johnson et al., Adv. Cancer Res. 60:1-40, 1993; and Wilkie etal., Curr. Biol. 5:500-507, 1995). Several isoforms of each FGFR havebeen identified and are the result of alternative splicing of theirmRNAs (Johnson et al., Mol. Cell. Biol. 11:4627-4634, 1995; andChellaiah et al., J. Biol. Chem. 269:11620-11627, 1994). A few of thereceptor variants that result from this alternative splicing havedifferent ligand binding specificities and affinities (Zimmer et al., J.Biol. Chem. 268:7899-7903, 1993; Cheon et al., Proc. Natl. Acad. Sci.U.S.A. 91:989-993, 1994; and Miki et al., Proc. Natl. Acad. Sci. U.S.A.89:246-250, 1992). Protein sequences for FGFR proteins and nucleic acidsencoding FGFR proteins are known in the art. Exemplary amino acidsequences for exemplary wildtype isoforms of FGFR1 are SEQ ID NO: 1 andSEQ ID NO: 2. Exemplary amino acid sequences for exemplary wildtypeisoforms of FGFR2 are SEQ ID NO: 2 and SEQ ID NO: 3. Exemplary aminoacid sequences for exemplary wildtype isoforms of FGFR3 are SEQ ID NO: 5and SEQ ID NO: 6. Exemplary amino acid sequences for exemplary wildypteisoforms of FGFR4 are SEQ ID NO: 7 and SEQ ID NO: 8.

Signaling by FGFRs regulates key biological processes including cellproliferation, survival, migration, and differentiation. Dysregulationof a FGFR gene, a FGFR protein, or expression or activity, or level ofthe same, has been associated with many types of cancer. For example,dysregulation of FGFRs can occur by multiple mechanisms, such as FGFRgene overexpression, FGFR gene amplification, activating mutations(e.g., point mutations or truncations), and chromosomal rearrangementsthat lead to FGFR fusion proteins. Dysregulation of a FGFR gene, a FGFRprotein, or expression or activity, or level of the same, can result in(or cause in part) the development of a variety of differentFGFR-associated cancers. Non-limiting examples of the types ofFGFR-associated cancers and the dysregulation of a FGFR gene, a FGFRprotein, or expression or activity, or level of the same, that causes(or causes in part) the development of the FGFR-associated cancers arelisted in Tables A-D.

For example, dysregulation of a FGFR1 gene, a FGFR1 protein, orexpression or activity, or level of the same, can include FGFR1 geneamplification, a FGFR1 gene fusion from those listed in Table C, and/orone or more point mutations selected from those listed in Table A (e.g.,one of more of T141R, R445W, N546K, K656E, and G818R). Dysregulation ofa FGFR2 gene, a FGFR2 protein, or expression or activity, or level ofthe same, can, e.g., include FGFR2 gene amplification, a FGFR2 genefusion from those listed in Table C, and/or one or more point mutationsselected from those listed in Table A (e.g., one or more of S252W,P253R, A315T, D336N, Y375C, C382R, V395D, D471N, I547V, N549K, N549K,N549Y, and K659E).

Dysregulation of a FGFR3 gene, a FGFR3 protein, or expression oractivity, or level of the same can, e.g., include FGFR3 geneamplification, a FGFR3 gene fusion from those listed in Table C, and/orone or more point mutations selected from those listed in Table A (e.g.,one or more of S131L, R248C, S249C, G370C, S371C, Y373C, G380R, R399C,E627K, K650E, K650M, V677I, and D785Y). Dysregulation of a FGFR4 gene, aFGFR4 protein, or expression or activity, or level of the same can,e.g., include FGFR4 gene amplification and/or one or more pointmutations selected from those listed in Table A (e.g., one or more ofR183S, R394Q, D425N, V510L, and R610H).

Additional examples of FGFR fusion proteins, FGFR point mutations, FGFRgene overexpression, or FGFR gene amplification that cause (or cause inpart) the development of a FGFR-associated cancer are described in: Wuet al., Cancer Discovery 3:636, 2013; Wesche et al., Biochem. J.437:199-213, 2011; Gallo et al., Cytokine Growth Factor Rev. 26:425-449,2015; Parker et al., J. Pathol. 232:4-15, 2014; Katoh et al., ExpertRev. Anticancer Res. 10:1375-1379, 2010; Chang et al., PLoS One9:e105524, 2014; Kelleher et al., Carcinogenesis 34:2198-2205, 2013;Katoh et al., Med. Res. Rev. 34:280-300, 2014; Knights et al.,Pharmacol. Therapeutics 125:105-117, 2010; Turner et al., Sci. Transl.Med. 2:62ps56, 2010; Dutt et al., PLoS One 6(6):e20351, 2011; Weiss etal., Sci. Transl. Med. 2:62ra93, 2010; Becker et al., J. Neurophatol.Exp. Neurol. 74:743-754, 2015; Byron et al., PLoS One 7(2):e30801, 2012;van Rhihn et al., Eur. J. Human Genetics 10:819-824, 2002; Hart et al.,Oncogene 19(29):3309-3320, 2000; Lin et al., Cancer Res. 68:664-673,2008; and Helsten et al., Clin. Cancer Res., e-publication dated Sep.15, 2015 (each of which is incorporated herein by reference). Additionalnon-limiting aspects and examples of FGFR fusion proteins, FGFR pointmutations, FGFR gene overexpression, or FGFR gene amplification aredescribed below.

Point Mutations

FGFR mutations that confer constitutive activation have been describedin a number of congenital skeletal disorders (Turner N, Grose R., NatRev Cancer 2010; 10:116-129). FGFRs have been identified as among themost commonly mutated kinase genes in human cancers, with mutations inFGFR2 and FGFR3 being most prevalent (Turner N., Grose R., Nat RevCancer 2010; 10:116-129). For example, approximately 50% to 60% ofnon-muscle invasive and 17% of high-grade bladder cancers possess FGFR3mutations that cause constitutive FGFR dimerization and activation(Cappellen D. et al., Nat Genet 1999; 23:18-20). Activating andoncogenic FGFR2 mutations located in the extracellular and kinasedomains of the receptor have been described in 12% of endometrialcarcinomas (Dutt A. et al., Proc Natl Acad Sci USA 2008; 105:8713-8717).Importantly, the FGFR2 mutations found in endometrial cancer confersensitivity to FGFR inhibition (Dutt A. et al., Proc Natl Acad Sci USA2008; 105:8713-8717). More recently, FGFR2 mutations have been describedin 5% of squamous non-small cell lung cancers (NSCLC; Hammerman P. etal., Genomic characterization and targeted therapeutics in squamous celllung cancer [abstract]. In: Proceedings of the 14th World Conference onLung Cancer; 2011 3-7 July; Aurora (Colo.): International Associationfor the Study of Lung Cancer; 2011). FGFR3 mutations in bladder cancerand FGFR2 mutations in endometrial cancer are mutually exclusive withmutations in HRAS and KRAS, respectively. In addition, mutations in theFGFR4 kinase domain have been found in the childhood soft tissue sarcomarhabdomyosarcoma, causing autophosphorylation and constitutive signaling(Taylor J G, et al., J Clin Invest 2009; 119:3395-407). FGFR1, FGFR2,FGFR3, and/or FGFR4 can include one, two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen,seventeen, eighteen, nineteen, or twenty different point mutations (ascompared to an appropriate corresponding wildtype FGFR1, FGFR2, FGFR3,or FGFR4 amino acid sequence, respectively). Non-limiting examples ofpoint mutations in FGFR1, FGFR2, FGFR3, or FGFR4 that are thought tocause (or cause in-part) a FGFR-associated cancer are listed in Table A.

FGFR Gene Amplification

FGFR gene amplification often leads to FGFR overexpression, which canprovoke ligand-independent signaling. In breast cancer, amplification ofthe genomic locus of FGFR1 (8p11-12) occurs in approximately 10% ofpredominantly estrogen receptor (ER)-positive patients (Taylor J G, etal., J Clin Invest 2009; 119:3395-4307). In vitro studies support thepotential oncogenic nature of FGFR1 amplification (Welm B E, et al., JCell Biol 2002; 157:703-14); however, due to the gene-dense nature ofthe 8p11-12 amplicon in breast cancer, there is continuing debate aboutthe identity of the driving oncogene. More recently. FGFR1 has beenfound to be amplified in 22% of squamous NSCLC (Weiss J, et al., SciTransl Med 2010; 2:62ra93), and these amplifications seem to conferdependence upon FGFR signaling. Unlike the broad amplicon containingFGFR1 found in breast cancers, the amplicon in lung is more focal; itremains to be seen if these differences influence the degree ofoncogenic addiction to FGFR1. FGFR2 amplifications have been reported inup to 10% of gastric cancers, most of which are diffuse-type withrelatively poor prognosis (Kunii K, et al., Cancer Res 2008;68:2340-2348). Further, in an FGFR2-amplified gastric cancer cell line,Snu-16, FGFR2 downregulation led to significant inhibition of cellgrowth and survival that further translated into tumor growth regressionin vivo (Xie L, et al., AZD4547, a potent and selective inhibitor ofFGF-receptor tyrosine kinases 1, 2 and 3, inhibits the growth ofFGF-receptor 2 driven gastric cancer models in vitro and in vivo. In:Proceedings of the American Association of Cancer Research AnnualMeeting; 2011 Apr. 2-6; Orlando (Fla.). Philadelphia (Pa.): AACR; 2011.Abstract nr 1643). In some gastric cancer cell lines, FGFR2amplification is accompanied by deletion of the coding exon locatedproximal to the C-terminus (Ueda T, et al., Cancer Res 1999;59:6080-6086). This deletion impedes receptor internalization, therebycontributing to constitutive activation of the receptor. The presence ofFGFR2 gene amplifications in gastric cancer is associated withsensitivity to inhibition of FGFR signaling by tyrosine kinaseinhibitors and monoclonal antibodies in preclinical models (Zhao G, etal., Mol Cancer Ther 2011; 10:2200-2210; Zhao W M, et al., Clin CancerRes 2010; 16:5750-5758). Non-limiting examples of FGFR-associatedcancers that are caused (or caused in-part) by the amplification and/oroverexpression of the FGFR1 gene, the FGFR2 gene, the FGFR3 gene, or theFGFR4 gene are listed in Table B.

TABLE B Overexpression or Amplification of FGFR Genes andFGFR-Associated Cancer FGFR Gene Type of Dysregulation FGFR-AssociatedCancer FGFR1 Amplification or Breast cancer or carcinoma (e.g.,Overexpression hormone receptor-positive breast cancer, ductal carcinomain situ (breast)), pancreatic ductal adenocarcinoma, pancreatic exocrinecarcinoma, smoking- associated lung cancer, small cell lung cancer, lungadenocarcinoma, non-small cell lung cancer, squamous cell lung cancer orcarcinoma, prostate cancer or carcinoma, ovarian cancer, fallopian tubecarcinoma, bladder cancer, rhabdomyosarcoma, head and neck carcinoma(e.g., head and neck squamous cell carcinoma), esophageal cancer (e.g.,esophageal squamous cell carcinoma), sarcoma (e.g., osteosarcoma),hepatocellular carcinoma, renal cell carcinoma, colorectal cancer (e.g.,colorectal adenocarcinoma), prostate cancer, salivary gland tumors,glioblastoma multiforme, urinary bladder cancer, urothelial carcinoma,carcinoma of unknown primary, squamous non- lung tumors, gastric cancer,gastroesophageal junction carcinoma, adenoid cystic carcinoma, analsquamous cell carcinoma, oral squamous cell carcinoma,cholangiocarcinoma, hemangioendothelioma, leiomyosarcoma, melanoma,neuroendocrine carcinoma, squamous cell carcinoma, uterinecarcinosarcoma FGFR2 Amplification Gastric cancer, gastroesophagealjunction adenocarcinoma, breast cancer (e.g., triple-negative breastcancer), colon cancer, colorectal cancer (e.g., colorectaladenocarcinoma), urothelial cancer, bladder adenocarcinoma, carcinoma ofunknown primary, cholangiocarcinoma, endometrial adenocarcinoma,esophageal adenocarcinoma, gallbladder carcinoma, ovarian cancer,fallopian tube carcinoma, pancreatic exocrine carcinoma, sarcoma,squamous cell carcinoma FGFR2 Overexpression Myxoid lipocarcinoma,rectal cancer, renal cell carcinoma, breast cancer FGFR3 Upregulation ofActivity Colorectal cancer, hepatocellular carcinoma, pancreaticexocrine carcinoma FGFR3 Overexpression Multiple myeloma, thyroidcarcinoma, FGFR3 Amplification Bladder cancer and salivary adenoidcystic cancer, urothelial cancer, breast cancer, carcinoid, carcinoma ofunknown primary, colorectal cancer (e.g., colorectal adenocarcinoma),gallbladder carcinoma, gastric cancer, gastroesophageal junctionadenocarcinoma, glioma, mesothelioma, non-small cell lung carcinoma,small cell lung cancer, ovarian cancer, fallopian tube carcinoma,pancreatic exocrine carcinoma FGFR4 Amplification Rhabdomyosarcoma,prostate cancer or carcinoma, breast cancer, urothelial cancer,carcinoid, carcinoma of unknown primary, esophageal adenocarcinoma, headand neck carcinoma, hepatocellular carcinoma, non-small cell lungcarcinoma, ovarian cancer, fallopian tube carcinoma, peritonealcarcinoma, renal cell carcinoma FGFR4 Upregulation of ActivityColorectal cancer, hepatocellular carcinoma, adrenal carcinoma, breastcancer FGFR4 Overexpression Pancreatic intraepithelial neoplasia, andpancreatic ductal adenocarcinoma

Fusion Proteins

Several FGFR translocations have been identified to play a role indefects in development and in a wide range of malignancies, wherebychromosomal rearrangement results in a nucleic acid sequence encoding afusion protein that includes a kinase domain of an FGFR protein and anamino acid sequence from a partner protein. In some examples, fusionproteins are located in the cytosol, do not undergo lysosomaldegradation, are not susceptible to feedback inhibition, and arepermanently dimerized in the absence of ligand. Such translocations canlead to FGFR overexpression, permanent dimerization of the fusionprotein-FGFR complex, and continuous signaling. The mechanism ofproliferation is dependent on the type of fusion protein and seems to bedisease specific (Jackson C C, et al., Hum Pathol 2010; 41:461-476). Forexample, a t(4;14) intergenic translocation, bringing FGFR3 and theadjacent Multiple Myeloma SET domain (MMSET) gene under the control ofthe Ig heavy chain (IGH) promoter, has been identified in 10% to 20% ofmultiple myelomas and is associated with poor prognosis and dependenceupon FGFR signaling (Chesi M, et al., Nat Genet 1997; 16:260-264; QingJ, et al., J Clin Invest 2009; 119:1216-1229). FGFR3 translocations arerarely found in prodromal conditions of multiple myeloma, implicatingthese translocations in the conversion to full multiple myeloma.Additional examples of FGFR fusion proteins and the specificFGFR-associated cancers that they cause (or cause in part) are listed inTable C. The expression of FGFR fusion proteins can, e.g., cause (orcause in part) cholangiocarcinoma, bladder cancer, lung cancer, andbreast cancer. Additional examples of FGFR fusion proteins are known inthe art.

Autocrine and Paracrine Signaling

Although many of the mechanisms discussed so far are the result ofgenetic dysregulation of the FGF/FGFR signaling axis, ligand-dependentsignaling is also likely to play a key role in cancer development (e.g.,described as “Upregulation of Activity” in Table 2). Autocrine FGFoverproduction has been reported in many tumor types (Turner N, GroseR., Nat Rev Cancer 2010; 10:116-129). In vitro studies have shown thatFGF5 overexpression has been associated with a number of tumor celllines (lung, esophagus, melanoma, colon, and prostate; Hanada K, et al.,Cancer Res 2001; 61:5511-5516), and in hepatocellular carcinomas (HCC),the upregulation of FGF2, 8, 17, and 18 initiates autocrine growthstimulation, cell survival, and neoangiogenesis (Uematsu S, et al., JGastroenterol Hepatol 2005; 20:583-588; Hu M C, et al., Mol Cell Biol1998; 18:6063-6074; Kin M, et al., J Hepatol 1997; 27:677-687;Gauglhofer C, et al., Hepatology 2011; 53:854-864). Further, HCC hasbeen found to develop in transgenic mice overexpressing the hormonalFGF19 (Nicholes K, et al., Am J Pathol 2002; 160:2295-2307), and FGF19is found on an amplicon on chromosome 11q that also invariably containsthe adjacent FGF3, FGF4, and Cyclin D1 (CCND1) genes. This amplicon isfound in various diseases, including head and neck squamous cellcarcinoma, breast cancer, and squamous NSCLC. Although there isuncertainty about the key oncogenic gene on this amplicon or apresumption that it is CCND1, genetic knockdown of FGF19 inhibits thegrowth of HCC cell lines carrying the amplicon (Sawey E T, et al.,Cancer Cell 2011; 19:347-358). Autocrine FGF2-FGFR1 feedback loops havealso been reported in NSCLC cell lines and in human melanomas grown assubcutaneous tumors in nude mice (Marek L, et al., Mol Pharmacol 2009;75:196-207; Wang Y, Becker D., Nat Med 1997; 3:887-893).

Paracrine production of FGFs has also been reported in multiple tumortypes. High levels of serum FGF2 have been observed in small cell lungcancer and are associated with a poor prognosis (Ruotsalainen T, et al.,Cancer Epidemiol Biomarkers Prev 2002; 11:1492-1495), possibly becauseof an FGF2-mediated cytoprotective effect, whereby the expression ofantiapoptotic proteins are upregulated, promoting resistance to currentanticancer treatments (Pardo O E, et al., EMBO J 2006; 25:3078-3088).Increased paracrine expression of one or more of FGF1, 2, 4, 5, 8, and18 has been found to promote tumor neoangiogenesis in preclinical modelsvia the main endothelial FGFRs, FGFR1 and 2 (Presta M, et al., CytokineGrowth Factor Rev 2005; 16:159-178). Poor prognosis has been associatedwith neoangiogenesis in ovarian cancer and melanomas (Birrer M J, etal., J Clin Oncol 2007; 25:2281-2287).

Altered FGFR mRNA Splicing

In addition to overexpression of FGFs, altered splicing of FGFR mRNAs isanother mechanism by which ligand-dependent signaling is upregulated.Altered FGFR mRNA splicing can allow tumor cells to be stimulated by abroader range of FGFs than would be capable under normal physiologicconditions (Zhang X, et al., J Biol Chem 2006; 281:15694-15700). Alteredsplicing of the IgIII domains in FGFRs 1, 2, and 3 can switch receptorbinding affinity in cancer cells towards FGFs found in the healthystroma, creating an aberrant paracrine signaling loop (Wesche J, HaglundK, Haugsten E M. et al., Biochem J 2011; 437:199-213). In bladder andprostate cancer cell lines, a switch from the FGFR2-IIIb isoform to theIIIc isoform has been associated with tumor progression,epithelial-mesenchymal transition, and increased invasiveness (Wesche J,et al., Biochem J 2011; 437:199-213).

Non-limiting examples of FGFR-associated cancers include urothelialcarcinoma, breast carcinoma or cancer (e.g., hormone receptor-positivebreast cancer, triple-negative breast cancer, neuroendocrine carcinomaof the breast, mammary carcinoma), endometriod endometrial cancer orendometrial cancer (e.g., endometrial adenocarcinoma), ovarian carcinomaor cancer (e.g., ovarian serous cancer), brain cancer (e.g., glioneuraltumors, glioma, pilocytic astrocytoma, rosette-forming glioneuraltumor), cholangiocarcinoma (e.g., intrahepatic cholangiocarcinoma,metastatic cholangiocarcinoma, medulloblastoma), gastric or stomachcancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors,lung cancer (e.g., non-small cell lung carcinoma or lung large cellcarcinoma, smoking-associated lung cancer, small cell lung cancer, lungadenocarcinoma, squamous cell lung cancer or carcinoma, lungneuroendocrine carcinoma), pancreatic cancer (e.g., pancreatic exocrinecarcinoma, pancreatic ductal adenocarcinoma, pancreatic intraepithelialneoplasia), prostate cancer, colorectal carcinoma or cancer, rectalcancer, renal cell carcinoma, neuroendocrine carcinoma, head and neck(squamous) carcinoma or head and neck adenoid cystic carcinoma, skincancer (e.g., melanoma), leiomyosarcoma, sarcoma (e.g., osteosarcoma orsoft tissue sarcoma), osteosarcoma, bladder cancer, uterine cancer,urinary bladder cancer, rhabdomyosarcoma (e.g., alveolarrhabdomyosarcoma or embryonal rhabdomyosarcoma), esophageal cancer(e.g., esophageal adenocarcinoma), hepatocellular carcinoma or livercancer, biliary tract cancer, salivary gland tumors (e.g., pleomorphicsalivary gland adenocarcinoma), glioblatoma multiforme, myxoidlipocarcinoma, oral cancer (e.g., oral squamous cell carcinoma), thyroidcancer or carcinoma, anaplastic thyroid carcinoma, adenoid cysticcarcinoma (e.g., salivary adenoid cystic cancer), glioblastomamultiforme, myeloproliferative disorders/hematological malignancies(e.g., 8p11 myeloproliferative syndrome, lymphoma (e.g., T-lymphoblasticlymphoma, T-cell lymphoma, B-cell lymphoma), leukemia (e.g., acutelymphoblatic leukemia (ALL), chronic myelogenous leukemia (CML), acutemyeloid leukemia (AML)), myeloproliferative neoplasm, myeloid andlymphoid neoplasms, stem cell myeloproliferative disorders,myeloproliferative disorder stem cell leukemiallymphoma syndrome,chronic myeloid disorder, myeloma (e.g., multiple myeloma)),phosphaturic mesenchymal tumor, cervical cancer (e.g., cervical squamouscell carcinoma), gallbladder cancer, spermatocytic seminoma, seborrheickeratosis, testicular cancer, mesothelioma, dysembryoplasticneuroepithelial tumor, and dedifferentiated liposarcoma. Additionalexamples of FGFR-associated cancers are listed in Tables 1-3.

Non-limiting examples of additional FGFR-associated diseases that arecaused by dysregulation of FGFR are listed in Table D. A subject havingany of the additional FGFR-associated diseases described herein or knownin the art can be treated by administering to the subject atherapeutically effective amount of a compound of General Formula I(e.g., any of the exemplary compounds described herein).

Additional point mutations in FGFR1, FGFR2, FGFR3, and FGFR4 have beenidentified to result in resistance of a cancer cell to a FGFR inhibitor.Non-limiting examples of these mutations are depicted in Table E. Insome embodiments, a FGFR-associated disorder (e.g., any of the cancersdescribed herein) can have one or more of the point mutations listed inTable D. Also provided herein are methods of treating a subject thatinclude identifying a subject having one or more of the point mutationslisted in Table D, and administering to the identified subject atherapeutically effective amount of a compound of General Formula I(e.g., any of the exemplary compounds described herein), or apharmaceutically acceptable salt of solvate thereof. Also provided aremethods of treating a subject that include administering to a subjectidentified as having one or more of the point mutations listed in TableD a therapeutically effective amount of a compound of General Formula I(e.g., any of the exemplary compounds described herein).

In some embodiments, provided herein is a method for treating a subjectdiagnosed with a FGFR-associated disorder (e.g., a FGFR-associatedcancer), that include administering to the subject a therapeuticallyeffective amount of a compound of General Formula I (e.g., any of theexemplary compounds described herein), or a pharmaceutically acceptablesalt or solvate thereof. For example, the FGFR-associated cancer can beany of exemplary FGFR-associated cancers described herein.

In some embodiments, the compounds of the present invention are usefulfor treating a FGFR-associated disease (e.g., a FGFR-associated cancer)in combination with one or more additional therapeutic agents ortherapies that work by the same or a different mechanism of action.

In some embodiments, the additional therapeutic agent(s) is selectedfrom the group of: receptor tyrosine kinase-targeted therapeutic agents,including cabozantinib, crizotinib, erlotinib, gefitinib, imatinib,lapatinib, nilotinib, pazopanib, pertuzumab, regorafenib, and sunitinib.

In some embodiments, the additional therapeutic agent(s) is selectedfrom signal transduction pathway inhibitors, including, e.g.,Ras-Raf-MEK-ERK pathway inhibitors (e.g., sorafenib, trametinib, orvemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (e.g., everolimus,rapamycin, perifosine, or temsirolimus) and modulators of the apoptosispathway (e.g., obataclax).

In some embodiments, the additional therapeutic agent(s) is selectedfrom the group of: cytotoxic chemotherapeutics, including, e.g., arsenictrioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin,cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel,doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan,lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel,pemetrexed, temozolomide, and vincristine.

In some embodiments, the additional therapeutic agent(s) is selectedfrom the group of angiogenesis-targeted therapies, including e.g.,aflibercept and bevacizumab.

In some embodiments, the additional therapeutic agent(s) is selectedfrom the group of immune-targeted agents, e.g., including aldesleukin,ipilimumab, lambrolizumab, nivolumab, and sipuleucel-T.

In some embodiments, the additional therapeutic agent(s) is selectedfrom agents active against the downstream FGFR pathway, including, e.g.,Ras, MEK, JNK, and p38 kinase inhibitor.

In some embodiments, the additional therapeutic agent or therapy isradiotherapy, including, e.g., radioiodide therapy, external-beamradiation, and radium 223 therapy. In some embodiments, the additionaltherapeutic agent(s) includes any one of the above listed therapies ortherapeutic agents which are standards of care in cancers wherein thecancer has a dysregulation of a FGFR gene, a FGFR protein, or expressionor activity, or level of the same.

Methods of detecting dysregulation of a FGFR gene, a FGFR protein, orexpression or activity, or level of the same, include, e.g., detectionof FGFR gene translocations, e.g., using Fluorescent In SituHybridization (FISH) (e.g., the commercially available kits from EmpireGenomics and Cell Signaling Technology).

In some embodiments, provided herein is a method of treating cancer(e.g., a FGFR-associated cancer) in a patient, comprising administeringto said subject a compound of General Formula I (e.g., any of theexemplary compounds described herein), or a pharmaceutically acceptablesalt or solvate thereof, in combination with at least one additionaltherapy or therapeutic agent selected from radiotherapy (e.g.,radioiodide therapy, external-beam radiation, or radium 223 therapy),cytotoxic chemotherapeutics (e.g., arsenic trioxide, bleomycin,cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide,cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin,etoposide, fluorouracil, gemcitabine, irinotecan, lomustine,methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed,temozolomide, or vincristine); tyrosine kinase targeted-therapeutics(e.g., afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib,erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib,panitumumab, pertuzumab, regorafenib, sunitinib, or trastuzumab); FGFRinhibitors (e.g., ARQ-087, AZD-4547, BGJ398, nintadanib (BIBF 1120),BLU9931, brivanib (BMS-582664), CH5183284, Dovitinib (TKI258, CHIR258),E-3810, EWMD-2076, JNJ-42756493, lenvatinib ((E7080), LY2874455,Orantinib (TSU-68, SU6668), PD089828, PD166866, PD173074, Ponatinib(AP-24534), Semaxanib (SU5416), SSR128129E, SU4984, SU5402, SUN11602),AB1010, BAY 1163877, Debio-1347, FGF401, FIIN-2, HMPL-453, MK-2461,pazopanib (Votrient, GW-786034), PD161570, PD173074, PF-477736,PHA-739358 (danusertib), PRN1371, regorafenib (Stivarga), SPP86, andTyrphostin AG 1296 and TAS120; apoptosis modulators and signaltransduction inhibitors (e.g. everolimus, perifosine, rapamycin,sorafenib, temsirolimus, trametinib, or vemurafenib); immune-targetedtherapies (e.g., aldesleukin, interferon alfa-2b, ipilimumab,lambrolizumab, nivolumab, prednisone, or sipuleucel-T); andangiogenesis-targeted therapies (e.g., aflibercept or bevacizumab),wherein the amount of the compound of General Formula I (e.g., any ofthe exemplary compounds described herein), or a pharmaceuticallyacceptable salt or solvate thereof, in combination with the additionaltherapy or therapeutic agent, is effective in treating said cancer.These additional therapeutic agents may be administered with one or moredoses of the compound of General Formula I, or the pharmaceuticallyacceptable salt or solvate thereof, as part of the same or separatedosage forms, via the same or different routes of administration, and onthe same or different administration schedules according to standardpharmaceutical practice known to one skilled in the art. In someembodiments, provided herein is a method of treating cancer (e.g., aFGFR-associated cancer) in a patient, comprising administering to saidsubject a compound of General Formula I (e.g., any of the exemplarycompounds described herein), or a pharmaceutically acceptable salt orsolvate thereof, in combination with at least one additional therapy ortherapeutic agent selected from radiotherapy (e.g., radioiodide therapy,external-beam radiation, or radium 223 therapy), cytotoxicchemotherapeutics (e.g., arsenic trioxide, bleomycin, cabazitaxel,capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine,dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide,fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate,mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, orvincristine), tyrosine kinase targeted-therapeutics (e.g., afatinib,cabozantinib, cetuximab, crizotinib, dabrafenib, erlotinib, gefitinib,imatinib, lapatinib, nilotinib, pazopanib, panitumumab, pertuzumab,regorafenib, or sunitinib), apoptosis modulators and signal transductioninhibitors (e.g. everolimus, perifosine, rapamycin, sorafenib,temsirolimus, trametinib, or vemurafenib), immune-targeted therapies(e.g., aldesleukin, interferon alfa-2b, ipilimumab, lambrolizumab,nivolumab, prednisone, or sipuleucel-T) and angiogenesis-targetedtherapies (e.g., aflibercept or bevacizumab), wherein the amount of thecompound of General Formula I (e.g., any of the exemplary compoundsdescribed herein), or a pharmaceutically acceptable salt or solvatethereof, in combination with the additional therapy or therapeuticagent, is effective in treating said cancer. These additionaltherapeutic agents may be administered with one or more doses of thecompound of General Formula I, or the pharmaceutically acceptable saltor solvate thereof, as part of the same or separate dosage forms, viathe same or different routes of administration, and on the same ordifferent administration schedules according to standard pharmaceuticalpractice known to one skilled in the art.

Also provided herein is (i) a pharmaceutical combination for treatingcancer (e.g., a FGFR-associated cancer) in a subject in need thereof,which comprises (a) a compound of General Formula I (e.g., any of theexemplary compounds described herein), or a pharmaceutically acceptablesalt or solvate thereof, (b) an additional therapeutic agent and (c)optionally at least one pharmaceutically acceptable carrier (e.g., forsimultaneous, separate or sequential use for the treatment of a cancer),wherein the amounts of the compound of General Formula I, or thepharmaceutically acceptable salt or solvate thereof and of theadditional therapeutic agent are together effective in treating saidcancer; (ii) a pharmaceutical composition including such a combination;(iii) the use of such a combination for the preparation of a medicamentfor the treatment of cancer (e.g., a FGFR-associated cancer); and (iv) acommercial package or product including such a combination as a combinedpreparation for simultaneous, separate or sequential use; and to amethod of treatment of cancer (e.g., FGFR-associated cancer) in asubject in need thereof.

Also provided are methods of treating a subject identified or diagnosedas having a FGFR-associated disease (e.g., a FGFR-associated cancer)(e.g., a subject that has been identified or diagnosed as having aFGFR-associated disease (e.g., a FGFR-associated cancer) through the useof a regulatory agency-approved, e.g., FDA-approved, kit for identifyingdysregulation of a FGFR gene, a FGFR protein, or expression or activity,or level of the same, in a subject or a biopsy sample from the subject)(e.g., any of the FGFR-associated cancers described herein or known inthe art) that include administering the subject a therapeuticallyeffective amount of a compound of General Formula I (e.g., any of theexemplary compounds described herein), or a pharmaceutically acceptablesalt or solvate thereof. Also provided is a compound of General FormulaI (e.g., any of the exemplary compounds described herein), or apharmaceutically acceptable salt or solvate thereof, for use in treatinga FGFR-associated disease (e.g., a FGFR-associated cancer) in a subjectidentified or diagnosed as having a FGFR-associated disease (e.g., aFGFR-associated cancer) (e.g., a subject that has been identified ordiagnosed as having a FGFR-associated cancer through the use of aregulatory agency-approved, e.g., FDA-approved, kit for identifyingdysregulation of a FGFR gene, a FGFR protein, or expression or activity,or level of the same, in a subject or a biopsy sample from the subject)(e.g., any of the FGFR-associated cancers described herein or known inthe art). Also provided is the use of a compound of General Formula I(e.g., any of the exemplary compounds described herein), or apharmaceutically acceptable salt or solvate thereof, for the manufactureof a medicament for treating a FGFR-associated disease (e.g.,FGFR-associated cancer) in a subject identified or diagnosed as having aFGFR-associated disease (e.g., FGFR-associated cancer) (e.g., a subjectthat has been identified or diagnosed as having a FGFR-associated cancerthrough the use of a regulatory agency-approved, e.g., FDA-approved, kitfor identifying dysregulation of a FGFR gene, a FGFR protein, orexpression or activity, or level of the same, in a subject or a biopsysample from the subject) (e.g., any of the FGFR-associated cancersdescribed herein or known in the art).

Also provided are methods of treating a subject (e.g., a subjectsuspected of having a FGFR-associated disease (e.g., a FGFR-associatedcancer), a subject presenting with one or more symptoms of aFGFR-associated disease (e.g., a FGFR-associated cancer), or a subjecthaving an elevated risk of developing a FGFR-associated disease (e.g.,FGFR-associated cancer)) that include performing an assay (e.g., anassay that utilizes next generation sequencing, immunohistochemistry, orbreak apart FISH analysis) (e.g., using a regulatory agency-approved,e.g., FDA-approved, kit) on a sample obtained from the subject todetermine whether the subject has dysregulation of a FGFR gene, a FGFRprotein, or expression or activity, or level of the same, andadministering (e.g., specifically or selectively administering) atherapeutically effective amount of a compound of General Formula I(e.g., any of the exemplary compounds described herein), or apharmaceutically acceptable salt or solvate thereof, to a subjectdetermined to have dysregulation of a FGFR gene, a FGFR protein, orexpression or activity, or levels of the same. Additional assays,non-limiting assays that may be used in these methods are describedherein. Additional assays are also known in the art. Also provided isuse of a compound of General Formula I (e.g., any of the exemplarycompounds described herein), or a pharmaceutically acceptable salt orsolvate thereof, for use in treating a FGFR-associated disease (e.g.,FGFR-associated cancer) in a subject identified or diagnosed as having aFGFR-associated disease (e.g., a FGFR-associated cancer) through a stepof performing an assay (e.g., an in vitro assay) (e.g., an assay thatutilizes next generation sequencing, immunohistochemistry, or breakapart FISH analysis) (e.g., using a regulatory agency-approved, e.g.,FDA-approved, kit) on a sample obtained from the subject to determinewhether the subject has dysregulation of a FGFR gene, a FGFR protein, orexpression or activity, or level of the same, where the presence ofdysregulation of a FGFR gene, a FGFR protein, or expression or activity,or level of the same, identifies that the subject has a FGFR-associateddisorder (e.g., FGFR-associated cancer). Also provided is the use of acompound of General Formula I (e.g., any of the exemplary compoundsdescribed herein), or a pharmaceutically acceptable salt or solvatethereof, for the manufacture of a medicament for treating aFGFR-associated disease (e.g., FGFR-associated cancer) in a subjectidentified or diagnosed as having a FGFR-associated disease (e.g.,FGFR-associated cancer) through a step of performing an assay (e.g., anin vitro assay) (e.g., an assay that utilizes next generationsequencing, immunohistochemistry, or break apart FISH analysis) (e.g.,using a regulatory agency-approved, e.g., FDA-approved, kit) on a sampleobtained from the subject to determine whether the subject hasdysregulation of a FGFR gene, a FGFR protein, or expression or activity,or level of the same, where the presence of dysregulation of a FGFRgene, a FGFR protein, or expression or activity, or level of the same,identifies that the subject has a FGFR-associated disease (e.g.,FGFR-associated cancer). Some embodiments of any of the methods or usesdescribed herein further include recording in the subject's clinicalrecord (e.g., a computer readable medium) that the subject determined tohave dysregulation of a FGFR gene, a FGFR protein, or expression oractivity, or level of the same, through the performance of the assay,should be administered a compound of General Formula I (e.g., any of theexemplary compounds described herein), or a pharmaceutically acceptablesalt or solvate thereof.

In some embodiments of any of the methods or uses described herein, thesubject has been identified or diagnosed as having a cancer withdysregulation of a FGFR gene, a FGFR protein, or expression or activity,or level of the same (e.g., as determined using a regulatoryagency-approved, e.g., FDA-approved, assay or kit). In some embodimentsof any of the methods or uses described herein, the subject has a tumorthat is positive for dysregulation of a FGFR gene, a FGFR protein, orexpression or activity, or level of the same (e.g., as determined usinga regulatory agency-approved assay or kit). In some embodiments of anyof the methods or uses described herein, the subject can be a subjectwith a tumor(s) that is positive for dysregulation of a FGFR gene, aFGFR protein, or expression or activity, or level of the same (e.g.,identified as positive using a regulatory agency-approved, e.g.,FDA-approved, assay or kit). In some embodiments of any of the methodsor uses described herein, the subject can be a subject whose tumors havedysregulation of a FGFR gene, a FGFR protein, or expression or activity,or a level of the same (e.g., where the tumor is identified as suchusing a regulatory agency-approved, e.g., FDA-approved, kit or assay).In some embodiments of any of the methods or uses described herein, thesubject is suspected of having a FGFR-associated cancer. In someembodiments of any of the methods or uses described herein, the subjecthas a clinical record indicating that the subject has a tumor that hasdysregulation of a FGFR gene, a FGFR protein, or expression or activity,or level of the same (and optionally the clinical record indicates thatthe subject should be treated with any of the compositions providedherein).

Also provided are methods of treating a subject that includeadministering a therapeutically effective amount of a compound ofGeneral Formula I (e.g., any of the exemplary compounds describedherein), or a pharmaceutically acceptable salt or solvate thereof, to asubject having a clinical record that indicates that the subject hasdysregulation of a FGFR gene, a FGFR protein, or expression or activity,or level of the same. Also provided is the use of a compound of GeneralFormula I (e.g., any of the exemplary compounds described herein), or apharmaceutically acceptable salt or solvate thereof, for the manufactureof a medicament for treating a FGFR-associated disease (e.g.,FGFR-associated cancer) in a subject having a clinical record thatindicates that the subject has dysregulation of a FGFR gene, a FGFRprotein, or expression or activity, or level of the same. Also providedis the use of a compound of General Formula I (e.g., any of theexemplary compounds described herein), or a pharmaceutically acceptablesalt or solvate thereof, for the manufacture of a medicament fortreating a FGFR-associated disease (e.g., a FGFR-associated cancer) in asubject having a clinical record that indicates that the subject hasdysregulation of a FGFR gene, a FGFR protein, or expression or activity,or level of the same. Some embodiments of these methods and uses canfurther include: a step of performing an assay (e.g., an in vitro assay)(e.g., an assay that utilizes next generation sequencing,immunohistochemistry, or break apart FISH analysis) (e.g., using aregulatory agency-approved, e.g., FDA-approved, kit) on a sampleobtained from the subject to determine whether the subject hasdysregulation of a FGFR gene, a FGFR protein, or expression or activity,or level of the same, and recording information in a subject's clinicalfile (e.g., a computer-readable medium) that the subject has beenidentified to have dysregulation of a FGFR gene, a FGFR protein, orexpression or activity, or level of the same.

Also provided are methods (e.g., in vitro methods) of selecting atreatment for a subject that include selecting a treatment includingadministration of a therapeutically effective amount of a compound ofGeneral Formula I (e.g., any of the exemplary compounds describedherein), or a pharmaceutically acceptable salt or solvate thereof, for asubject identified or diagnosed as having a FGFR-associated disease(e.g., a FGFR-associated cancer) (e.g., a subject that has beenidentified or diagnosed as having a FGFR-associated cancer through theuse of a regulatory agency-approved, e.g., FDA-approved, kit foridentifying dysregulation of a FGFR gene, a FGFR protein, or expressionor activity, or level of the same, in a subject or a biopsy sample fromthe subject) (e.g., any of the FGFR-associated cancers described hereinor known in the art). Some embodiments can further include administeringthe selected treatment to the subject identified or diagnosed as havinga FGFR-associated disease (e.g., a FGFR-associated cancer). Someembodiments can further include a step of performing an assay (e.g., anin vitro assay) (e.g., an assay that utilizes next generationsequencing, immunohistochemistry, or break apart FISH analysis) (e.g.,using a regulatory agency-approved, e.g., FDA-approved, kit) on a sampleobtained from the subject to determine whether the subject hasdysregulation of a FGFR gene, a FGFR protein, or expression or activity,or level of the same, and identifying or diagnosing a subject determinedto have dysregulation of a FGFR gene, a FGFR protein, or expression oractivity, or level of the same, as having a FGFR-associated disease(e.g., a FGFR-associated cancer).

Also provided are methods of selecting a treatment for a subject thatinclude administration of a therapeutically effective amount of acompound of General Formula I (e.g., any of the exemplary compoundsdescribed herein), or a pharmaceutically acceptable salt or solvatethereof, wherein the methods include a step of performing an assay(e.g., an in vitro assay) (e.g., an assay that utilizes next generationsequencing, immunohistochemistry, or break apart FISH analysis) (e.g.,using a regulatory agency-approved, e.g., FDA-approved, kit) on a sampleobtained from the subject to determine whether the subject hasdysregulation of a FGFR gene, a FGFR protein, or expression or activity,or level of the same, and identifying or diagnosing a subject determinedto have dysregulation of a FGFR gene, a FGFR protein, or expression oractivity, or level of the same, as having a FGFR-associated cancer, andselecting a therapeutic treatment including administration of atherapeutically effective amount of a compound of General Formula I(e.g., any of the exemplary compounds described herein), or apharmaceutically acceptable salt or solvate thereof, for the subjectidentified or diagnosed as having a FGFR-associated disease (e.g., aFGFR-associated cancer). Some embodiments further include administeringthe selected treatment to the subject identified or diagnosed as havinga FGFR-associated disorder (e.g., a FGFR-associated cancer).

Also provided are methods of selecting a subject for treatment includingadministration of a therapeutically effective amount of a compound ofGeneral Formula I (e.g., any of the exemplary compounds describedherein), or a pharmaceutically acceptable salt or solvate thereof, thatinclude selecting, identifying, or diagnosing a subject having aFGFR-associated disorder (e.g., a FGFR-associated cancer), and selectingthe subject for treatment including administration of a therapeuticallyeffective amount of a compound of General Formula I (e.g., any of theexemplary compounds described herein), or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, identifying or diagnosinga subject as having a FGFR-associated disease (e.g., an FGFR-associatedcancer) can include a step of performing an assay (e.g., an in vitroassay) (e.g., an assay that utilizes next generation sequencing,immunohistochemistry, or break apart FISH analysis) (e.g., using aregulatory agency-approved, e.g., FDA-approved, kit) on a sampleobtained from the subject to determine whether the subject hasdysregulation of a FGFR gene, a FGFR protein, or expression or activity,or level of the same, and identifying or diagnosing a subject determinedto have dysregulation of a FGFR gene, a FGFR protein, or expression oractivity, or level of the same, as having a FGFR-associated disorder(e.g., a FGFR-associated cancer). In some embodiments, the selecting atreatment can be used as part of a clinical study that includesadministration of various treatments of an FGFR-associated disorder(e.g., a FGFR-associated cancer).

In some embodiments of any of the methods or uses described herein, anassay used determine whether the subject has dysregulation of a FGFRgene, a FGFR protein, or expression or activity, or level of the same,using a sample (e.g., a biological sample or a biopsy sample (e.g., aparaffin-embedded biopsy sample) from a subject (e.g., a subjectsuspected of having a FGFR-associated disease (e.g., a FGFR-associatedcancer), a subject having one or more symptoms of a FGFR-associateddisease (e.g., a FGFR-associated cancer), and/or a subject that has anincreased risk of developing a FGFR-associated disease (e.g., aFGFR-associated cancer)) can include, for example, next generationsequencing, immunohistochemistry, fluorescence microscopy, break apartFISH analysis, Southern blotting, Western blotting, FACS analysis,Northern blotting, and PCR-based amplification (e.g., RT-PCR). As iswell-known in the art, the assays are typically performed, e.g., with atleast one labelled nucleic acid probe or at least one labelled antibodyor antigen-binding fragment thereof. Assays can utilize other detectionmethods known in the art for detecting dysregulation of a FGFR gene, aFGFR protein, or expression or activity, or levels of the same (see,e.g., the references cited herein).

Exemplary assays for detecting dysregulation of a FGFR gene, a FGFRprotein, or expression or activity, or levels of the same arecommercially available, e.g., FGFR Pathway Mutation PCR Array (Qiagen),HTG Edge FGFR Expression Assay (HTG Molecular Diagnostics), HTScan® FGFReceptor 1 Kinase Assay Kit (Cell Signaling Technology), Vysis LSIIGH/FGFR3 Dual Color, Dual Fusion Translocation Probe (AbbottMolecular), FGFR1 FISH Probe (Empire Genomics), FGFR1 FISH (SonicGenomics), FISH IGH/FGFR3 (Quest Diagnostics), FGFR1 (8p11) [RUO] (LeicaBiosystems), FGFR1 Break Apart FISH Probe (Empire Genomics),FGFR2/CEN10p FISH Probe (Abnova Corporation), FGFR2 (10q26) [ASR](LeicaBiosystems), Anti-FGFR-4 (IN), Z-FISH (AnaSpec), ZytoLight® SPEC FGFR2Break Apart Probe (Bio-Optica), FGFR3 (4p16.3) (ZytoVision), andZytoLight® SPEC FGFR3/CEN4 Dual Color Probe (ZytoVision). Additionalassays for detecting dysregulation of a FGFR gene, a FGFR protein, orexpression or activity or levels of the same are known in the art.

Also provided are methods of increasing the time of remission of aFGFR-associated cancer in a patient that include (a) selecting,identifying, or diagnosing a patient as having a FGFR-associated cancer(e.g., any of the FGFR-associated cancers described herein), and (b)administering a therapeutically effective amount of a compound ofGeneral Formula I (e.g., any of the exemplary compounds describedherein), or a pharmaceutically acceptable salt or solvate thereof. Alsoprovided are methods of increasing the time of remission of aFGFR-associated cancer in a patient that include administering atherapeutically effective amount of a compound of General Formula I(e.g., any of the exemplary compounds described herein), or apharmaceutically acceptable salt or solvate thereof to a patient havinga FGFR-associated cancer (e.g., any of the exemplary FGFR-associatedcancers described herein). In some examples of any of the methods ofincreasing the time of remission of a FGFR-associated cancer in apatient, the increase in the time of remission is compared to a controlpatient (e.g., a patient or a population of patients having the same ora similar type of FGFR-associated cancer). In some examples, the patientis not yet in remission. In other examples, the patient is already inremission. In some examples, the increase in remission is astatistically significant increase. In some examples, the increase inthe time of remission is about 1 day to about 10 years, about 9.5 years,about 9 years, about 8.5 years, about 8 years, about 7.5 years, about 7years, about 6.5 years, about 6 years, about 5.5 years, about 5 years,about 4.5 years, about 4 years, about 3.5 years, about 3 years, about2.5 years, about 2 years, about 1.5 years, about 1 year, about 10months, about 8 months, about 6 months, about 4 months, about 2 months,about 1 month, or about 2 weeks; about 2 weeks to about 10 years, about9.5 years, about 9 years, about 8.5 years, about 8 years, about 7.5years, about 7 years, about 6.5 years, about 6 years, about 5.5 years,about 5 years, about 4.5 years, about 4 years, about 3.5 years, about 3years, about 2.5 years, about 2 years, about 1.5 years, about 1 year,about 10 months, about 8 months, about 6 months, about 4 months, about 2months, or about 1 month; about 1 month to about 10 years, about 9.5years, about 9 years, about 8.5 years, about 8 years, about 7.5 years,about 7 years, about 6.5 years, about 6 years, about 5.5 years, about 5years, about 4.5 years, about 4 years, about 3.5 years, about 3 years,about 2.5 years, about 2 years, about 1.5 years, about 1 year, about 10months, about 8 months, about 6 months, about 4 months, or about 2months; about 2 month to about 10 years, about 9.5 years, about 9 years,about 8.5 years, about 8 years, about 7.5 years, about 7 years, about6.5 years, about 6 years, about 5.5 years, about 5 years, about 4.5years, about 4 years, about 3.5 years, about 3 years, about 2.5 years,about 2 years, about 1.5 years, about 1 year, about 10 months, about 8months, about 6 months, or about 4 months; about 4 month to about 10years, about 9.5 years, about 9 years, about 8.5 years, about 8 years,about 7.5 years, about 7 years, about 6.5 years, about 6 years, about5.5 years, about 5 years, about 4.5 years, about 4 years, about 3.5years, about 3 years, about 2.5 years, about 2 years, about 1.5 years,about 1 year, about 10 months, about 8 months, or about 6 months; about6 month to about 10 years, about 9.5 years, about 9 years, about 8.5years, about 8 years, about 7.5 years, about 7 years, about 6.5 years,about 6 years, about 5.5 years, about 5 years, about 4.5 years, about 4years, about 3.5 years, about 3 years, about 2.5 years, about 2 years,about 1.5 years, about 1 year, about 10 months, or about 8 months; about8 month to about 10 years, about 9.5 years, about 9 years, about 8.5years, about 8 years, about 7.5 years, about 7 years, about 6.5 years,about 6 years, about 5.5 years, about 5 years, about 4.5 years, about 4years, about 3.5 years, about 3 years, about 2.5 years, about 2 years,about 1.5 years, about 1 year, or about 10 months; about 10 month toabout 10 years, about 9.5 years, about 9 years, about 8.5 years, about 8years, about 7.5 years, about 7 years, about 6.5 years, about 6 years,about 5.5 years, about 5 years, about 4.5 years, about 4 years, about3.5 years, about 3 years, about 2.5 years, about 2 years, about 1.5years, or about 1 year; about 1 year to about 10 years, about 9.5 years,about 9 years, about 8.5 years, about 8 years, about 7.5 years, about 7years, about 6.5 years, about 6 years, about 5.5 years, about 5 years,about 4.5 years, about 4 years, about 3.5 years, about 3 years, about2.5 years, about 2 years, or about 1.5 years; about 1.5 years to about10 years, about 9.5 years, about 9 years, about 8.5 years, about 8years, about 7.5 years, about 7 years, about 6.5 years, about 6 years,about 5.5 years, about 5 years, about 4.5 years, about 4 years, about3.5 years, about 3 years, about 2.5 years, to about 2 years; about 2years to about 10 years, about 9.5 years, about 9 years, about 8.5years, about 8 years, about 7.5 years, about 7 years, about 6.5 years,about 6 years, about 5.5 years, about 5 years, about 4.5 years, about 4years, about 3.5 years, about 3 years, or about 2.5 years; about 2.5years to about 10 years, about 9.5 years, about 9 years, about 8.5years, about 8 years, about 7.5 years, about 7 years, about 6.5 years,about 6 years, about 5.5 years, about 5 years, about 4.5 years, about 4years, about 3.5 years, or about 3 years; about 3 years to about 10years, about 9.5 years, about 9 years, about 8.5 years, about 8 years,about 7.5 years, about 7 years, about 6.5 years, about 6 years, about5.5 years, about 5 years, about 4.5 years, about 4 years, or about 3.5years; about 3.5 years to about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, about 7 years,about 6.5 years, about 6 years, about 5.5 years, about 5 years, about4.5 years, or about 4 years; about 4 years to about 10 years, about 9.5years, about 9 years, about 8.5 years, about 8 years, about 7.5 years,about 7 years, about 6.5 years, about 6 years, about 5.5 years, about 5years, or about 4.5 years; about 4.5 years to about 10 years, about 9.5years, about 9 years, about 8.5 years, about 8 years, about 7.5 years,about 7 years, about 6.5 years, about 6 years, about 5.5 years, or about5 years; about 5 years to about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, about 7 years,about 6.5 years, about 6 years, or about 5.5 years; about 5.5 years toabout 10 years, about 9.5 years, about 9 years, about 8.5 years, about 8years, about 7.5 years, about 7 years, about 6.5 years, or about 6years; about 6 years to about 10 years, about 9.5 years, about 9 years,about 8.5 years, about 8 years, about 7.5 years, about 7 years, or about6.5 years; about 6.5 years to about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, or about 7years; about 7 years to about 10 years, about 9.5 years, about 9 years,about 8.5 years, about 8 years, or about 7.5 years; about 7.5 years toabout 10 years, about 9.5 years, about 9 years, about 8.5 years, orabout 8 years; about 8 years to about 10 years, about 9.5 years, about 9years, or about 8.5 years; about 8.5 years to about 10 years, about 9.5years, or about 9 years; about 9 years to about 10 years or about 9.5years; or about 9.5 years to about 10 years (e.g., compared to a controlpatient, e.g., a patient or a population of patients having the same ora similar type of FGFR-associated cancer).

Also provided is a compound of General Formula I or pharmaceuticallyacceptable salt or solvate thereof for use in increasing the time ofremission of a FGFR-associated cancer in a patient. Also provided is theuse of a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof in the manufacture of a medicament forincreasing the time of remission of a FGFR-associated cancer in apatient.

Methods for determining whether or not a patient is in remission areknown by those skilled in the art. For example, a PET scan, MRI, CTscan, ultrasound, and X-ray of the patient's body may be obtained, andsuch data can be used to determine whether or not a patient is inremission. In some examples, diagnostic tests can be performed onsamples from a patient (e.g., a blood sample or a biopsy) to determinewhether or not the patient is still in remission.

Also provided are methods of increasing the time of survival of apatient having a FGFR-associated cancer that include: selecting,diagnosing, or identifying a patient as having a FGFR-associated cancer;and administering to a subject selected, diagnosed, or identified ashaving a FGFR-associated cancer a therapeutically effective amount of acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof. Also provided are methods of increasing the time ofsurvival of a patient having a FGFR-associated cancer that includeadministering to a subject having a FGFR-associated cancer atherapeutically effective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof. In some embodimentsof any of the methods of increasing the time of survival of a subjecthaving a FGFR-associated cancer, the increase in the time of survival iscompared to a control patient (e.g., a patient or a population ofpatients having the same or a similar type of FGFR-associated cancer).In some examples, the patient can have an early stage of aFGFR-associated cancer (e.g., Stage 1 or 2). In some embodiments, thepatient can have a late stage of a FGFR-associated cancer (e.g., Stage 3or 4). In some examples, the increase in the time of survival is astatistically significant increase. In some examples, the increase inthe time of survival is about 1 day to about 40 years, about 38 years,about 36 years, about 34 years, about 32 years, about 30 years, about 28years, about 26 years, about 24 years, about 22 years, about 20 years,about 18 years, about 16 years, about 14 years, about 12 years, about 10years, about 9.5 years, about 9 years, about 8.5 years, about 8 years,about 7.5 years, about 7 years, about 6.5 years, about 6 years, about5.5 years, about 5 years, about 4.5 years, about 4 years, about 3.5years, about 3 years, about 2.5 years, about 2 years, about 1.5 years,about 1 year, about 10 months, about 8 months, about 6 months, about 4months, about 2 months, about 1 month, or about 2 weeks; about 2 weeksto about 40 years, about 38 years, about 36 years, about 34 years, about32 years, about 30 years, about 28 years, about 26 years, about 24years, about 22 years, about 20 years, about 18 years, about 16 years,about 14 years, about 12 years, about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, about 7 years,about 6.5 years, about 6 years, about 5.5 years, about 5 years, about4.5 years, about 4 years, about 3.5 years, about 3 years, about 2.5years, about 2 years, about 1.5 years, about 1 year, about 10 months,about 8 months, about 6 months, about 4 months, about 2 months, or about1 month; about 1 month to about 40 years, about 38 years, about 36years, about 34 years, about 32 years, about 30 years, about 28 years,about 26 years, about 24 years, about 22 years, about 20 years, about 18years, about 16 years, about 14 years, about 12 years, about 10 years,about 9.5 years, about 9 years, about 8.5 years, about 8 years, about7.5 years, about 7 years, about 6.5 years, about 6 years, about 5.5years, about 5 years, about 4.5 years, about 4 years, about 3.5 years,about 3 years, about 2.5 years, about 2 years, about 1.5 years, about 1year, about 10 months, about 8 months, about 6 months, about 4 months,or about 2 months; about 2 months to about 40 years, about 38 years,about 36 years, about 34 years, about 32 years, about 30 years, about 28years, about 26 years, about 24 years, about 22 years, about 20 years,about 18 years, about 16 years, about 14 years, about 12 years, about 10years, about 9.5 years, about 9 years, about 8.5 years, about 8 years,about 7.5 years, about 7 years, about 6.5 years, about 6 years, about5.5 years, about 5 years, about 4.5 years, about 4 years, about 3.5years, about 3 years, about 2.5 years, about 2 years, about 1.5 years,about 1 year, about 10 months, about 8 months, about 6 months, or about4 months; about 4 months to about 40 years, about 38 years, about 36years, about 34 years, about 32 years, about 30 years, about 28 years,about 26 years, about 24 years, about 22 years, about 20 years, about 18years, about 16 years, about 14 years, about 12 years, about 10 years,about 9.5 years, about 9 years, about 8.5 years, about 8 years, about7.5 years, about 7 years, about 6.5 years, about 6 years, about 5.5years, about 5 years, about 4.5 years, about 4 years, about 3.5 years,about 3 years, about 2.5 years, about 2 years, about 1.5 years, about 1year, about 10 months, about 8 months, or about 6 months; about 6 monthsto about 40 years, about 38 years, about 36 years, about 34 years, about32 years, about 30 years, about 28 years, about 26 years, about 24years, about 22 years, about 20 years, about 18 years, about 16 years,about 14 years, about 12 years, about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, about 7 years,about 6.5 years, about 6 years, about 5.5 years, about 5 years, about4.5 years, about 4 years, about 3.5 years, about 3 years, about 2.5years, about 2 years, about 1.5 years, about 1 year, about 10 months, orabout 8 months; about 8 months to about 40 years, about 38 years, about36 years, about 34 years, about 32 years, about 30 years, about 28years, about 26 years, about 24 years, about 22 years, about 20 years,about 18 years, about 16 years, about 14 years, about 12 years, about 10years, about 9.5 years, about 9 years, about 8.5 years, about 8 years,about 7.5 years, about 7 years, about 6.5 years, about 6 years, about5.5 years, about 5 years, about 4.5 years, about 4 years, about 3.5years, about 3 years, about 2.5 years, about 2 years, about 1.5 years,about 1 year, or about 10 months; about 10 months to about 40 years,about 38 years, about 36 years, about 34 years, about 32 years, about 30years, about 28 years, about 26 years, about 24 years, about 22 years,about 20 years, about 18 years, about 16 years, about 14 years, about 12years, about 10 years, about 9.5 years, about 9 years, about 8.5 years,about 8 years, about 7.5 years, about 7 years, about 6.5 years, about 6years, about 5.5 years, about 5 years, about 4.5 years, about 4 years,about 3.5 years, about 3 years, about 2.5 years, about 2 years, about1.5 years, or about 1 year; about 1 year to about 40 years, about 38years, about 36 years, about 34 years, about 32 years, about 30 years,about 28 years, about 26 years, about 24 years, about 22 years, about 20years, about 18 years, about 16 years, about 14 years, about 12 years,about 10 years, about 9.5 years, about 9 years, about 8.5 years, about 8years, about 7.5 years, about 7 years, about 6.5 years, about 6 years,about 5.5 years, about 5 years, about 4.5 years, about 4 years, about3.5 years, about 3 years, about 2.5 years, about 2 years, or about 1.5years; about 1.5 year to about 40 years, about 38 years, about 36 years,about 34 years, about 32 years, about 30 years, about 28 years, about 26years, about 24 years, about 22 years, about 20 years, about 18 years,about 16 years, about 14 years, about 12 years, about 10 years, about9.5 years, about 9 years, about 8.5 years, about 8 years, about 7.5years, about 7 years, about 6.5 years, about 6 years, about 5.5 years,about 5 years, about 4.5 years, about 4 years, about 3.5 years, about 3years, about 2.5 years, or about 2 years; about 2 year to about 40years, about 38 years, about 36 years, about 34 years, about 32 years,about 30 years, about 28 years, about 26 years, about 24 years, about 22years, about 20 years, about 18 years, about 16 years, about 14 years,about 12 years, about 10 years, about 9.5 years, about 9 years, about8.5 years, about 8 years, about 7.5 years, about 7 years, about 6.5years, about 6 years, about 5.5 years, about 5 years, about 4.5 years,about 4 years, about 3.5 years, about 3 years, or about 2.5 years; about2.5 year to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, about 26 years,about 24 years, about 22 years, about 20 years, about 18 years, about 16years, about 14 years, about 12 years, about 10 years, about 9.5 years,about 9 years, about 8.5 years, about 8 years, about 7.5 years, about 7years, about 6.5 years, about 6 years, about 5.5 years, about 5 years,about 4.5 years, about 4 years, about 3.5 years, or about 3 years; about3 year to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, about 26 years,about 24 years, about 22 years, about 20 years, about 18 years, about 16years, about 14 years, about 12 years, about 10 years, about 9.5 years,about 9 years, about 8.5 years, about 8 years, about 7.5 years, about 7years, about 6.5 years, about 6 years, about 5.5 years, about 5 years,about 4.5 years, about 4 years, or about 3.5 years; about 3.5 years toabout 40 years, about 38 years, about 36 years, about 34 years, about 32years, about 30 years, about 28 years, about 26 years, about 24 years,about 22 years, about 20 years, about 18 years, about 16 years, about 14years, about 12 years, about 10 years, about 9.5 years, about 9 years,about 8.5 years, about 8 years, about 7.5 years, about 7 years, about6.5 years, about 6 years, about 5.5 years, about 5 years, about 4.5years, or about 4 years; about 4 years to about 40 years, about 38years, about 36 years, about 34 years, about 32 years, about 30 years,about 28 years, about 26 years, about 24 years, about 22 years, about 20years, about 18 years, about 16 years, about 14 years, about 12 years,about 10 years, about 9.5 years, about 9 years, about 8.5 years, about 8years, about 7.5 years, about 7 years, about 6.5 years, about 6 years,about 5.5 years, about 5 years, or about 4.5 years; about 4.5 years toabout 40 years, about 38 years, about 36 years, about 34 years, about 32years, about 30 years, about 28 years, about 26 years, about 24 years,about 22 years, about 20 years, about 18 years, about 16 years, about 14years, about 12 years, about 10 years, about 9.5 years, about 9 years,about 8.5 years, about 8 years, about 7.5 years, about 7 years, about6.5 years, about 6 years, about 5.5 years, or about 5 years; about 5years to about 40 years, about 38 years, about 36 years, about 34 years,about 32 years, about 30 years, about 28 years, about 26 years, about 24years, about 22 years, about 20 years, about 18 years, about 16 years,about 14 years, about 12 years, about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, about 7 years,about 6.5 years, about 6 years, or about 5.5 years; about 5.5 years toabout 40 years, about 38 years, about 36 years, about 34 years, about 32years, about 30 years, about 28 years, about 26 years, about 24 years,about 22 years, about 20 years, about 18 years, about 16 years, about 14years, about 12 years, about 10 years, about 9.5 years, about 9 years,about 8.5 years, about 8 years, about 7.5 years, about 7 years, about6.5 years, or about 6 years; about 6 years to about 40 years, about 38years, about 36 years, about 34 years, about 32 years, about 30 years,about 28 years, about 26 years, about 24 years, about 22 years, about 20years, about 18 years, about 16 years, about 14 years, about 12 years,about 10 years, about 9.5 years, about 9 years, about 8.5 years, about 8years, about 7.5 years, about 7 years, or about 6.5 years; about 6.5years to about 40 years, about 38 years, about 36 years, about 34 years,about 32 years, about 30 years, about 28 years, about 26 years, about 24years, about 22 years, about 20 years, about 18 years, about 16 years,about 14 years, about 12 years, about 10 years, about 9.5 years, about 9years, about 8.5 years, about 8 years, about 7.5 years, or about 7years, about 7 years to about 40 years, about 38 years, about 36 years,about 34 years, about 32 years, about 30 years, about 28 years, about 26years, about 24 years, about 22 years, about 20 years, about 18 years,about 16 years, about 14 years, about 12 years, about 10 years, about9.5 years, about 9 years, about 8.5 years, about 8 years, or about 7.5years; about 7.5 years to about 40 years, about 38 years, about 36years, about 34 years, about 32 years, about 30 years, about 28 years,about 26 years, about 24 years, about 22 years, about 20 years, about 18years, about 16 years, about 14 years, about 12 years, about 10 years,about 9.5 years, about 9 years, about 8.5 years, or about 8 years; about8 years to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, about 26 years,about 24 years, about 22 years, about 20 years, about 18 years, about 16years, about 14 years, about 12 years, about 10 years, about 9.5 years,about 9 years, or about 8.5 years; about 8.5 years to about 40 years,about 38 years, about 36 years, about 34 years, about 32 years, about 30years, about 28 years, about 26 years, about 24 years, about 22 years,about 20 years, about 18 years, about 16 years, about 14 years, about 12years, about 10 years, about 9.5 years, or about 9 years; about 9 yearsto about 40 years, about 38 years, about 36 years, about 34 years, about32 years, about 30 years, about 28 years, about 26 years, about 24years, about 22 years, about 20 years, about 18 years, about 16 years,about 14 years, about 12 years, about 10 years, or about 9.5 years;about 9.5 years to about 40 years, about 38 years, about 36 years, about34 years, about 32 years, about 30 years, about 28 years, about 26years, about 24 years, about 22 years, about 20 years, about 18 years,about 16 years, about 14 years, about 12 years, or about 10 years; about10 years to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, about 26 years,about 24 years, about 22 years, about 20 years, about 18 years, about 16years, about 14 years, or about 12 years; about 12 years to about 40years, about 38 years, about 36 years, about 34 years, about 32 years,about 30 years, about 28 years, about 26 years, about 24 years, about 22years, about 20 years, about 18 years, about 16 years, or about 14years; about 14 years to about 40 years, about 38 years, about 36 years,about 34 years, about 32 years, about 30 years, about 28 years, about 26years, about 24 years, about 22 years, about 20 years, about 18 years,or about 16 years; about 16 years to about 40 years, about 38 years,about 36 years, about 34 years, about 32 years, about 30 years, about 28years, about 26 years, about 24 years, about 22 years, about 20 years,or about 18 years; about 18 years to about 40 years, about 38 years,about 36 years, about 34 years, about 32 years, about 30 years, about 28years, about 26 years, about 24 years, about 22 years, or about 20years; about 20 years to about 40 years, about 38 years, about 36 years,about 34 years, about 32 years, about 30 years, about 28 years, about 26years, about 24 years, or about 22 years; about 22 years to about 40years, about 38 years, about 36 years, about 34 years, about 32 years,about 30 years, about 28 years, about 26 years, or about 24 years; about24 years to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, about 30 years, about 28 years, or about 26years; about 26 years to about 40 years, about 38 years, about 36 years,about 34 years, about 32 years, about 30 years, or about 28 years; about28 years to about 40 years, about 38 years, about 36 years, about 34years, about 32 years, or about 30 years; about 30 years to about 40years, about 38 years, about 36 years, about 34 years, or about 32years; about 32 years to about 40 years, about 38 years, about 36 years,or about 34 years; about 34 years to about 40 years, about 38 years, orabout 36 years; about 36 years to about 40 years or about 38 years; orabout 38 years to about 40 years (e.g., compared to a control patient,e.g., a patient or a population of patients having the same or a similartype of FGFR-associated cancer).

Also provided is the use of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof for increasing thetime of survival of a patient having a FGFR-associated cancer. Alsoprovided is the use of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof for the manufactureof a medicament for increasing the time of survival of a patient havinga FGFR-associated cancer.

Also provided are methods of decreasing the risk of developing ametastasis or an additional metastasis in a patient having aFGFR-associated cancer that include: selecting, identifying, ordiagnosing a patient as having a FGFR-associated cancer, andadministering a therapeutically effective amount of a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof to the patient selected, identified, or diagnosed as having aFGFR-associated cancer. Also provided are methods of decreasing the riskof developing a metastasis or an additional metastasis in a patienthaving a FGFR-associated cancer that includes administering atherapeutically effective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvent thereof to a patient havinga FGFR-associated cancer. The decrease in the risk of developing ametastasis or an additional metastasis in a patient having aFGFR-associated cancer can be compared to the risk of developing ametastasis or an additional metastasis in the patient prior totreatment, or as compared to a patient or a population of patientshaving a similar or the same FGFR-associated cancer that has received notreatment or a different treatment. The decrease in the risk ofdeveloping a metastasis or an additional metastasis can be about 1% toabout 99%, about 95%, about 90%, about 85%, about 80%, about 75%, about70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%,about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, orabout 5%; about 5% to about 99%, about 95%, about 90%, about 85%, about80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%,about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about15%, or about 10%; about 10% to about 99%, about 95%, about 90%, about85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%,about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about20%, or about 15%; about 15% to about 99%, about 95%, about 90%, about85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%,about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, orabout 20%; about 20% to about 99%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about50%, about 45%, about 40%, about 35%, about 30%, or about 25%; about 25%to about 99%, about 95%, about 90%, about 85%, about 80%, about 75%,about 70%, about 65%, about 60%, about 55%, au bout 45%, about 40%,about 35%, or about 30%; about 30% to about 99%, about 95%, about 90%,about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about55%, about 50%, about 45%, about 40%, or about 35%; about 35% to about99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%,about 65%, about 60%, about 55%, about 50%, about 45%, or about 40%;about 40% to about 99%, about 95%, about 90%, about 85%, about 80%,about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, orabout 45%; about 45% to about 99%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, orabout 50%; about 50% to about 99%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, or about 55%;about 55% to about 99%, about 95%, about 90%, about 85%, about 80%,about 75%, about 70%, about 65%, or about 60%; about 60% to about 99%,about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, orabout 65%; about 65% to about 99%, about 95%, about 90%, about 85%,about 80%, about 75%, or about 70%; about 70% to about 99%, about 95%,about 90%, about 85%, about 80%, or about 75%; about 75% to about 99%,about 95%, about 90%, about 85%, or about 80%; about 80% to about 99%,about 95%, about 90%, or about 85%; about 85% to about 99%, about 95%,or about 90%; about 90% to about 99% or about 90%; or about 95% to about99% as compared to the risk of developing a metastasis or an additionalmetastasis in the patient prior to treatment, or as compared to apatient or a population of patients having a similar or the sameFGFR-associated cancer that has received no treatment or a differenttreatment.

In some examples, the risk of developing a metastasis or an additionalmetastasis is over about 2 weeks, 1 month, 1.5 months, 2 months, 2.5months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5months, 6 months, 6.5 months, 7 months, 7.5 months, 8 months, 8.5months, 9 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5months, 12 months, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 7.5years, 8 years, 8.5 years, 9 years, 9.5 years, or 10 years.

Also provided is the use of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof for decreasing therisk of developing a metastasis or an additional metastasis in a patienthaving a FGFR-associated cancer. Also provided is the use of a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof for the manufacture of a medicament for decreasing the risk ofdeveloping a metastasis or an additional metastasis in a patient havinga FGFR-associated cancer.

Also provided are methods of increasing sensitivity of a resistantcancer cell to an anti-cancer drug that include: selecting, identifying,or diagnosing a patient as having a resistant cancer cell (e.g., aresistant FGFR-associated cancer cell, e.g., a cancer cell identified ashaving one or more of the point mutations listed in Table E), andadministering to the selected, identified, or diagnosed subject atherapeutically effective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof. Also provided aremethods of increasing sensitivity of a resistant cancer cell to ananti-cancer drug that include administering to a patient having aresistant cancer cell to an anti-cancer drug a therapeutically effectiveamount of a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof. Some embodiments of any of thesemethods further include administering the anti-cancer drug to thepatient. In such examples, the anti-cancer drug can be co-administeredwith the compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof. In some examples, the anti-cancer drug can beadministered at substantially the same time as the compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof. Insome examples, a first dose of the compound of General Formula I isadministered prior to the first dose of the anti-cancer compound. Insome examples, a first dose of the anti-cancer compound is administeredprior to the first dose of the compound of General Formula I or apharmaceutically acceptable salt or solvate thereof. In some examples,the increase in the sensitivity of the resistant cancer cell to theanti-cancer drug can result in a decrease in the rate of growth and/orproliferation of the resistant cancer cell when contacted with theanti-cancer drug and at least one of the compounds described herein, ofbetween about 1% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%,55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%; about 2% toabout 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%,35%, 30%, 25%, 20%, 15%, 10%, or 5%; about 3% to about 100%, 95%, 90%,85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%,15%, 10%, or 5%; about 5% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%,65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%; about 5%to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%,40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%; about 5% to about 100%, 95%,90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%,20%, 15%, or 10%; about 10% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%,65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%; about5% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%,40%, 35%, 30%, 25%, 20%, or 15%; about 15% to about 100%, 95%, 90%, 85%,80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%,10%, or 5%; about 5% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%,60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, or 20%; about 20% to about 100%,95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%,25%, 20%, 15%, 10%, or 5%; about 5% to about 100%, 95%, 90%, 85%, 80%,75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, or 25%; about 25% toabout 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%,35%, 30%, 25%, or 20%; about 20% to about 100%, 95%, 90%, 85%, 80%, 75%,70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%;about 5% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%,50%, 45%, 40%, 35%, or 30%; about 30% to about 100%, 95%, 90%, 85%, 80%,75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, or 35%; about 35% to 100%, 95%,90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40%; about 40% toabout 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, or 45%;about 45% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or50%; about 50% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, or55%; about 55% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, or 60%;about 60% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, or 65%; about 65%to about 100%, 95%, 90%, 85%, 80%, 75%, or 70%; about 70% to about 100%,95%, 90%, 85%, 80%, or 75%; about 75% to about 100%, 95%, 90%, 85%, or80%; about 80% to about 100%, 95%, 90%, or 85%; about 85% to about 100%,95%, or 90%; about 90% to about 100% or 95%; or about 95% to about 100%,as compared to the rate of growth and/or proliferation of a resistantcancer cell when contacted with the anti-cancer drug alone.

A method of treating an angiogenesis-related disorder (e.g., any of theangiogenesis-related disorders described herein or known in the art) ina patient that include: identifying, selecting, or diagnosing aangiogenesis-related disorder in a patient, and administering to theidentified, selected, or diagnosed patient with a therapeuticallyeffective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof. A method oftreating an angiogenesis-related disorder in a patient that includesadministering a therapeutically effective amount of a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solventthereof to a patient having an angiogenesis-related disorder. In someexamples, the treating can result in a decrease in the diameter of ablood vessel and/or a decrease in the number of blood vessels in atissue in need of a reduction in the number of blood vessels (e.g., ascompared to the diameter of the blood vessel and/or the number of bloodvessels in the tissue in the patient prior to treatment). In someexamples the methods can result in, e.g., a decrease in the diameter ofa blood vessel of about 1% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%,45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%; about 2% to about 80%,75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or5%; about 3% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%,30%, 25%, 20%, 15%, 10%, or 5%; about 5% to about 80%, 75%, 70%, 65%,60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%; about 10% toabout 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%,or 15%; about 15% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%,35%, 30%, 25%, or 20%; about 20% to about 80%, 75%, 70%, 65%, 60%, 55%,50%, 45%, 40%, 35%, 30%, or 25%; about 25% to about 80%, 75%, 70%, 65%,60%, 55%, 50%, 45%, 40%, 35%, or 30%; about 30% to about 80%, 75%, 70%,65%, 60%, 55%, 50%, 45%, 40%, or 35%; about 35% to about 80%, 75%, 70%,65%, 60%, 55%, 50%, 45%, or 40%; about 40% to about 80%, 75%, 70%, 65%,60%, 55%, 50%, or 45%; about 45% to about 80%, 75%, 70%, 65%, 60%, 55%,or 50%; about 50% to about 80%, 75%, 70%, 65%, 60%, or 55%; about 55% toabout 80%, 75%, 70%, 65%, or 60%; about 60% to about 80%, 75%, 70%, or65%; about 65% to about 80%, 75%, or 70%; about 70% to about 80% or 75%,or about 75% to about 80% (e.g., as compared to the diameter of theblood vessel in the patient prior to treatment). In some examples themethods can result in, e.g., a decrease in the number of blood vesselsin a tissue in need of a reduction in the number of blood vessels ofabout 5% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%,25%, 20%, 15%, or 10%; about 10% to about 80%, 75%, 70%, 65%, 60%, 55%,50%, 45%, 40%, 35%, 30%, 25%, 20%, or 15%; about 15% to about 80%, 75%,70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, or 20%; about 20% orabout 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, or 25%;about 25% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, or30%; about 30% to about about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%,40%, or 35%; about 35% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%,or 40%; about 40% to about 80%, 75%, 70%, 65%, 60%, 55%, 50%, or 45%;about 45% to about 80%, 75%, 70%, 65%, 60%, 55%, or 50%; about 50% toabout 80%, 75%, 70%, 65%, 60%, or 55%; about 55% to about 80%, 75%, 70%,65%, or 60%; about 60% to about 80%, 75%, 70%, or 65%; about 65% toabout 80%, 75%, or 70%; about 70% to about 80% or 75%; or about 75% toabout 80% (e.g., as compared to the diameter of the blood vessel and/orthe number of blood vessels in the tissue in the patient prior totreatment). These methods can also result in a decrease in the rate offormation of new blood vessels in a tissue in need thereof in a patienthaving an angiogenesis-related disorder (e.g., as compared to the rateof formation of new blood vessels in the tissue in the patient prior totreatment, or the rate of formation of new blood vessels in a patient ora population of patients having the same or similar angiogenesis-relateddisorder). The decrease in the rate of formation of a new blood vesselsin a tissue in need thereof in a patient having an angiogenesis-relateddisorder can be about 1% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%,65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%; about5% to about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%,40%, 35%, 30%, 25%, 20%, 15%, or 10%; about 10% to about 100%, 95%, 90%,85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, or15%; about 15% to 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%,50%, 45%, 40%, 35%, 30%, 25%, or 20%; about 20% to 100%, 95%, 90%, 85%,80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, or 25%; about 25%to 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%,35%, or 30%; about 30% to 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%,55%, 50%, 45%, 40%, or 35%; about 35% to 100%, 95%, 90%, 85%, 80%, 75%,70%, 65%, 60%, 55%, 50%, 45%, or 40%; about 40% to 100%, 95%, 90%, 85%,80%, 75%, 70%, 65%, 60%, 55%, 50%, or 45%; about 45% to 100%, 95%, 90%,85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50%; about 50% to 100%, 95%, 90%,85%, 80%, 75%, 70%, 65%, 60%, or 55%; about 55% to 100%, 95%, 90%, 85%,80%, 75%, 70%, 65%, or 60%; about 60% to 100%, 95%, 90%, 85%, 80%, 75%,70%, or 65%; about 65% to 100%, 95%, 90%, 85%, 80%, 75%, or 70%; about70% to 100%, 95%, 90%, 85%, 80%, or 75%; about 75% to 100%, 95%, 90%,85%, or 80%; about 80% to 100%, 95%, 90%, or 85%; about 85% to 100%,95%, or 90%; about 90% to about 100% or 95%; or about 95% to about 100%(e.g., as compared to the rate of formation of new blood vessels in thetissue in the patient prior to treatment, or the rate of formation ofnew blood vessels in a patient or a population of patients having thesame or similar angiogenesis-related disorder).

Also provided is the use of a compound of General Formula I or apharmaceutically acceptable salt or solvent thereof for treating anangiogenesis-related disorder in a patient. Also provided is the use ofa compound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof in the manufacture of a medicament for treating anangiogenesis-related disorder in a patient.

Also provided are methods for treating cancer in a patient in needthereof, the method comprising: (a) determining if the cancer in thepatient is an FGFR-associated cancer (e.g., using a regulatory-agencyapproved, e.g., FDA-approved, kit for identifying dysregulation ofdysregulation of a FGFR gene, a FGFR protein, or expression or activityor level of any of the same, in a patient or a biopsy sample from thepatient, or by performing any of the non-limiting examples of assaysdescribed herein); and (b) if the cancer in the patient is determined tobe an FGFR-associated cancer, administering to the patient atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof.

Also provided is use of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof for use in treating anFGFR-associated cancer (e.g., any of the FGFR-associated cancersdescribed herein) in a patient identified or diagnosed as having anFGFR-associated cancer through a step of performing an assay (e.g., anin vitro assay) (e.g., an assay that utilizes next generationsequencing, immunohistochemistry, or break apart FISH analysis) (e.g.,using a regulatory agency-approved, e.g., FDA-approved kit) on a sampleobtained from the patient to determine whether the patient hasdysregulation of a FGFR gene, a FGFR protein, or expression or activityor level of any of the same, where the presence of dysregulation of aFGFR gene, a FGFR protein, or expression or activity or level of any ofthe same, identifies that the patient has an FGFR-associated cancer.Also provided is the use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof for the manufactureof a medicament for treating an FGFR-associated cancer in a patientidentified or diagnosed as having an FGFR-associated cancer through astep of performing an assay (e.g., an in vitro assay) (e.g., an assaythat utilizes next generation sequencing, immunohistochemistry, or breakapart FISH analysis) (e.g., using a regulatory agency-approved, e.g.,FDA-approved, kit) on a sample obtained from the patient to determinewhether the patient has a dysregulation of a FGFR gene, a FGFR protein,or expression or activity or level of any of the same where the presenceof dysregulation of a FGFR gene, a FGFR protein, or expression oractivity or level of any of the same, identifies that the patient has anFGFR-associated cancer. Some embodiments of any of the methods or usesdescribed herein further include recording in the patient's clinicalrecord (e.g., a computer readable medium) that the patient determined tohave dysregulation of a FGFR gene, a FGFR protein, or expression oractivity or level of any of the same, through the performance of theassay, should be administered a compound of Formula I or apharmaceutically acceptable salt or solvate thereof.

Also provided is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment of a cancer(e.g., an FGFR-associated cancer) in a patient in need thereof or apatient identified or diagnosed as having an FGFR-associated cancer(e.g., a patient that has been identified or diagnosed as having anFGFR-associated cancer through the use of a regulatory agency-approved,e.g., FDA-approved, kit for identifying dysregulation of a FGFR gene, aFGFR protein, or expression or activity or level of any of the same, ina patient or a biopsy sample from the sample) (e.g., any of theFGFR-associated cancers described herein or known in the art). Alsoprovided is the use of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof for the manufacture of a medicamentfor treating a cancer (e.g., an FGFR-associated cancer) in a patientidentified or diagnosed as having an FGFR-associated cancer (e.g., apatient that has been identified or diagnosed as having anFGFR-associated cancer through the use of a regulatory agency-approved,e.g., FDA-approved, kit for identifying dysregulation of a FGFR gene, aFGFR protein, or expression or activity or level of any of the same, ina patient or a biopsy sample from the patient) (e.g., any of theFGFR-associated cancers described herein or known in the art).

In some embodiments of any of the methods or uses described herein, thepatient has been identified or diagnosed as having a cancer withdysregulation of a FGFR gene, a FGFR protein, or expression or activityor level of any of the same (e.g., as determined using a regulatoryagency-approved, e.g., FDA-approved, assay or kit). In some embodimentsof any of the methods or uses described herein, the patient has a tumorthat is positive for dysregulation of a FGFR gene, a FGFR protein, orexpression or activity or level of any of the same (e.g., as determinedusing a regulatory-agency-approved assay or kit). In some embodiments ofany of the methods or uses described herein, the patient can be apatient with a tumor(s) that is positive for dysregulation of a FGFRgene, a FGFR protein, or expression or activity or level of any of thesame (e.g., identified as positive using a regulatory agency-approved,e.g., FDA-approved, assay or kit). In some embodiments of any of themethods or uses described herein, the patient can be a patient whosetumors have dysregulation of a FGFR gene, a FGFR protein, or expressionor activity or level of any of the same (e.g., where the tumor isidentified as such using a regulatory agency-approved, e.g.,FDA-approved, kit or assay). In some embodiments of any of the methodsor uses described herein, the patient is suspected of having anFGFR-associated cancer. In some embodiments of any of the methods oruses described herein, the patient has a clinical record indicating thatthe patient has a tumor that has dysregulation of a FGFR gene, a FGFRprotein, or expression or activity or level of any of the same (andoptionally the clinical record indicates that the patient should betreated with any of the compounds of Formula I or a pharmaceuticallyacceptable salts or solvates thereof or compositions provided herein).

Also provided herein are methods of selecting a treatment for a patientthat include administration of a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof that include a step of performing an assay (e.g., an in vitroassay) (e.g., an assay that utilizes next generation sequencing,immunohistochemistry, or break apart FISH analysis) (e.g., using aregulatory agency-approved, e.g., FDA-approved, kit) on a sampleobtained from the patient to determine whether the patient hasdysregulation of a FGFR gene, a FGFR protein, or expression or activityor level of any of the same, identifying or diagnosing a patientdetermined to have dysregulation of a FGFR gene, a FGFR protein, orexpression or activity or level of any of the same, as having anFGFR-associated cancer, and selecting a therapeutic treatment includingadministration of a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof tothe patient identified or diagnosed as having an FGFR-associated cancer.Some embodiments further include administering the selected treatment tothe patient identified or diagnosed as having an FGFR-associated cancer.

In some embodiments of any of the methods or uses described herein, thecancer (e.g., FGFR-associated cancer) is a hematological cancer. In someembodiments of any of the methods or uses described herein, the cancer(e.g., an FGFR-associated cancer) is a solid tumor. In some embodimentsof any of the methods or uses described herein, the cancer (e.g.,FGFR-associated cancer) is any of the exemplary cancers (e.g., any ofthe exemplary FGFR-associated cancers) described herein.

Also provided herein is a method of treating a disease or disordermediated by FGFR (e.g., dysregulation of a FGFR gene, a FGFR protein, orexpression or activity or level of any of the same) in a patient in needof such treatment, the method comprising administering to the patient atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof. For example, the FGFR-associated disease can be anyof the FGFR-associated cancers described herein or known in the art.

Although the genetic basis of tumorigenesis may vary between differentcancer types, the cellular and molecular mechanisms required formetastasis appear to be similar for all solid tumor types. During ametastatic cascade, the cancer cells lose growth inhibitory response,undergo alterations in adhesiveness and produce enzymes that can degradeextracellular matrix components. This leads to detachment of tumor cellsfrom the original tumor, infiltration into the circulation through newlyformed vasculature (e.g., lymph vessels or blood vessels), migration andextravasation of the tumor cells at favorable distant sites, where theymay form colonies. A number of genes have been identified as beingpromoters or suppressors of metastasis. FGFR proteins have beenimplicated for a role in metastasis (Qian et al., Oncogene 33:3411-3421,2014).

Accordingly, also provided herein are methods for inhibiting,preventing, aiding in the prevention, or decreasing the symptoms ofmetastasis of a cancer (e.g., a FGFR-associated cancer) in a patient inneed thereof, the method comprising administering to the patient atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. Such methods can beused in the treatment of one or more of the cancers described herein. Insome embodiments, the cancer is an FGFR-associated cancer. In someembodiments, the compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof is used in combination with an additionaltherapy or another therapeutic agent, including a chemotherapeuticagent, such as a kinase inhibitor.

Also provided is a method for inhibiting activity of FGFR1, FGFR2, FGFR3and/or FGFR4 in a mammalian cell, comprising contacting the cell with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof. In one embodiment, the contacting is performed in vitro. Inanother embodiment, the contacting is performed in vivo (e.g., in ahuman). In one embodiment, when the contacting is performed in vivo, themethod can include administering an effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof to asubject. In some embodiments, the mammalian cell is a mammalian cancercell. In one embodiment, the mammalian cancer cell is any cancer asdescribed herein. In some embodiments, the mammalian cancer cell is anFGFR-associated cancer cell.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” an FGFR with a compound provided herein includesthe administration of a compound provided herein to an individual orpatient, such as a human, having FGFR1, FGFR2, FGFR3 and/or FGFR4, aswell as, for example, introducing a compound provided herein into asample containing a cellular or purified preparation containing theFGFR1, FGFR2, FGFR3 and/or FGFR4.

In the field of medical oncology it is normal practice to use acombination of different forms of treatment to treat each patient withcancer. In medical oncology the other component(s) of such conjointtreatment or therapy in addition to compositions provided herein may be,for example, surgery, radiotherapy, and chemotherapeutic agents, such askinase inhibitors, signal transduction inhibitors and/or monoclonalantibodies. Compounds of Formula I therefore may also be useful asadjuvants to cancer treatment, that is, they can be used in combinationwith one or more additional therapies or therapeutic agents, for examplea chemotherapeutic agent that works by the same or by a differentmechanism of action.

In some embodiments of any the methods described herein, the compound ofFormula I (or a pharmaceutically acceptable salt or solvate thereof) isadministered in combination with a therapeutically effective amount ofat least one additional therapeutic agent selected from one or moreadditional therapies or therapeutic (e.g., chemotherapeutic) agents.Non-limiting examples of additional therapeutic agents include: receptortyrosine kinase-targeted therapeutic agents, such as afatinib,cabozantinib, cetuximab, crizotinib, dabrafenib, erlotinib, gefitinib,imatinib, lapatinib, lestaurtinib, nilotinib, pazopanib, panitumumab,pertuzumab, sunitinib, AG 879, AZ-23, AZ623, Go 6976, GNF-5837, GTx-186,GW 441756, LOXO-101, MGCD516, RPI-1, RXDX101, and TSR-011; FGFR-targetedtherapeutic agents, such as signal transduction pathway inhibitors, suchas Ras-Raf-MEK-ERK pathway inhibitors (e.g., binimetinib, selumetinib,encorafinib, sorafenib, trametinib, and vemurafenib), PI3K-Akt-mTOR-S6Kpathway inhibitors (e.g. everolimus, rapamycin, perifosine,temsirolimus), other kinase inhibitors, such as baricitinib, brigatinib,capmatinib, danusertib, ibrutinib, milciclib, quercetin, regorafenib,ruxolitinib, semaxanib, AP32788, BLU285, BLU554, INCB39110, INCB40093,INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS-1286937, PF477736, PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX103,RXDX106, RXDX108, and TG101209; FGFR inhibitors (e.g., ARQ-087,AZD-4547, BGJ398, nintadanib (BIBF 1120), BLU9931, brivanib(BMS-582664), CH5183284, Dovitinib (TKI258, CHIR258), E-3810, EWMD-2076,JNJ-42756493, lenvatinib ((E7080), LY2874455, Orantinib (TSU-68,SU6668), PD089828, PD166866, PD173074, Ponatinib (AP-24534), Semaxanib(SU5416), SSR128129E, SU4984, SU5402, SUN11602), AB1010, BAY 1163877,Debio-1347, FGF401, FIIN-2, HMPL-453, MK-2461, pazopanib (Votrient,GW-786034), PD161570, PD173074, PF-477736, PHA-739358 (danusertib),PRN1371, regorafenib (Stivarga), SPP86, and Tyrphostin AG 1296, andTAS120; checkpoint inhibitors, such as ipilimumab, tremelimumab,nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C, BMS-936559,BMS-956559, BMS-935559 (MDX-1105), AMP-224, and pembrolizumab;modulators of the apoptosis pathway (e.g. obataclax); cytotoxicchemotherapeutics, such as arsenic trioxide, bleomycin, cabazitaxel,capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine,dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide,fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate,mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, andvincristine; angiogenesis-targeted therapies, such as aflibercept andbevacizumab; immune-targeted agents, such as aldesleukin, interferonalfa-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, sipuleucel-T;radiotherapy, such as radioiodide therapy, external-beam radiation, andradium 223 therapy.

Yet other therapeutic agents that can be administered with a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof,include FGFR inhibitors such as those described, for example, LY2874455(Lilly), dovitinib (TKI258) (Novartis), BGJ398 (Novartis), AZD4547(AstraZeneca), ponatinib (Ariad), E-3810 (EOS), JNJ-42756493(Astex/Janssen), and ARQ 087 (ArQule).

In some embodiments, the amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof is, in combinationwith the at least one additional therapeutic agent, effective intreating the cancer (e.g., an FGFR-associated cancer). The at least oneadditional therapeutic agent may be administered with a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof aspart of the same or separate dosage forms, via the same or differentroutes of administration, and on the same or different administrationschedules according to standard pharmaceutical practice known to oneskilled in the art.

Also provided herein is (i) a pharmaceutical combination for treatingcancer in a patient in need thereof, which comprises (a) a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, (b)at least one additional therapeutic agent (e.g., any of the exemplaryadditional therapeutic agents described herein or known in the art), and(c) optionally at least one pharmaceutically acceptable carrier forsimultaneous, separate or sequential use for the treatment of cancer,wherein the amounts of the compound of Formula I or pharmaceuticallyacceptable salt or solvate thereof and of the additional therapeuticagent are together effective in treating the cancer; (ii) apharmaceutical composition comprising such a combination; (iii) the useof such a combination for the preparation of a medicament for thetreatment of cancer; and (iv) a commercial package or product comprisingsuch a combination as a combined preparation for simultaneous, separateor sequential use; and to a method of treatment of cancer a patient inneed thereof. In one embodiment the patient is a human.

The term “pharmaceutical combination”, as used herein, refers to apharmaceutical therapy resulting from the mixing or combining of morethan one active ingredient and includes both fixed and non-fixedcombinations of the active ingredients. The term “fixed combination”means that a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and at least one additional therapeutic agent (e.g.,a chemotherapeutic agent), are both administered to a patientsimultaneously in the form of a single composition or dosage. The term“non-fixed combination” means that a compound of Formula I or apharmaceutically acceptable salt or solvate thereof and at least oneadditional therapeutic agent (e.g., chemotherapeutic agent) areadministered to a patient as separate compositions or dosages, eithersimultaneously, concurrently or sequentially with variable interveningtime limits, wherein such administration provides effective levels ofthe two or more compounds in the body of the patient. These also applyto cocktail therapies, e.g. the administration of three or more activeingredients

Accordingly, also provided herein is a method of treating cancer,comprising administering to a patient in need thereof a pharmaceuticalcombination for treating cancer which comprises (a) a compound ofFormula I or pharmaceutically acceptable salt or solvate thereof, (b) anadditional therapeutic agent, and (c) optionally at least onepharmaceutically acceptable carrier for simultaneous, separate orsequential use for the treatment of cancer, wherein the amounts of thecompound of Formula I or pharmaceutically acceptable salt or solvatethereof and the additional therapeutic agent are together effective intreating the cancer. In one embodiment, the compound of Formula I orpharmaceutically acceptable salt or solvate thereof, and the additionaltherapeutic agent are administered simultaneously as separate dosages.In one embodiment, the compound of Formula I or pharmaceuticallyacceptable salt or solvate thereof, and the additional therapeutic agentare administered as separate dosages sequentially in any order, injointly therapeutically effective amounts, e.g. in daily orintermittently dosages. In one embodiment, compound of Formula I orpharmaceutically acceptable salt or solvate thereof, and the additionaltherapeutic agent are administered simultaneously as a combined dosage.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment of anFGFR-associated disease or disorder as defined hereinabove.

Also provided herein are methods of treating a FGFR-associated disease(e.g., a FGFR-associated cancer, e.g., any of the FGFR-associatedcancers described herein or known in the art) in a patient that include:(a) administering to a patient identified or diagnosed as having anFGFR-associated disease (e.g., an FGFR-associated cancer) one or moredoses of a first FGFR inhibitor over a treatment period; (b) determininga level of phosphate in a biological sample including blood, serum, orplasma obtained from the patient after the treatment period; (c)selecting a patient having an elevated level of phosphate in thebiological sample as compared to a reference level of phosphate; and (d)ceasing administration of the first FGFR inhibitor (or instructing theselected patient to cease administration) and initiating administrationof a therapeutically effective amount of a compound of Formula I orpharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalagent or composition comprising a compound of Formula I orpharmaceutically acceptable salt or solvate thereof (e.g., any of thepharmaceutical agents or compositions described herein), to the selectedpatient. Some embodiments of these methods can further includeidentifying or diagnosing a patient as having a FGFR-associated disease(e.g., a FGFR-associated cancer) using any of the methods describedherein.

In certain embodiments of these methods, the treatment period can befrom about 1 day to about 30 days (e.g., from about 1 day to about 15days; e.g. about 7 days; e.g., from about 16 days to about 30 days,e.g., about 21 days). In other embodiments of these methods, thetreatment period can be from 30 days to about 12 months (e.g., fromabout 30 days to about 9 months, from about 30 days to about 6 months,from about 30 days to about 120 days, from about 30 days to about 90days, from about 30 days to about 60 days). In still other embodiments,the treatment period is 7 days or more or 21 days or more (e.g., morethan 7 days or more than 21 days to about 12 months, more than 7 days ormore than 21 days to about 9 months, more than 7 days or more than 21days to about 6 months, more than 7 days or more than 21 days to about120 days, more than 7 days or more than 21 days to about 90 days, morethan 7 days or more than 21 days to about 60 days, more than 7 days ormore than 21 days to about 30 days).

In some embodiments of these methods, the treatment period is at leastor about 1 day, at least or about 2 days, at least or about 3 days, atleast or about 4 days, at least or about 5 days, at least or about 6days, at least or about 7 days, at least or about 8 days, at least orabout 9 days, at least or about 10 days, at least or about 11 days, atleast or about 12 days, at least or about 13 days, at least or about 14days, at least or about 15 days, at least or about 16 days, at least orabout 17 days, at least or about 18 days, at least or about 19 days, atleast or about 20 days, at least or about 21 days, at least or about 22days, at least or about 23 days, at least or about 24 days, at least orabout 25 days, at least or about 26 days, at least or about 27 days, atleast or about 28 days, at least or about 29 days, at least or about 30days, at least or about 31 days, at least or about 45 days, at least orabout 60 days, at least or about 90 days, at least or about 120 days, atleast or about 6 months, at least or about 9 months, at least or about12 months.

As used herein, the term “first FGFR inhibitor” means an FGFR inhibitorthat is not a compound of Formula I or a salt or solvate thereof, or apharmaceutical composition that includes a compound of Formula I or asalt or solvate thereof. Non-limiting examples of first FGFR inhibitorinclude JNJ-42756493 or BGJ398.

In some embodiments, the treatment period is at least 7 days (e.g., atleast or about 8 days, at least or about 9 days, at least or about 10days, at least or about 11 days, at least or about 12 days, at least orabout 13 days, at least or about 14 days, at least or about 15 days, atleast or about 16 days, at least or about 17 days, at least or about 18days, at least or about 19 days, at least or about 20 days, at least orabout 21 days, at least or about 22 days, at least or about 23 days, atleast or about 24 days, at least or about 25 days, at least or about 26days, at least or about 27 days, at least or about 28 days, at least orabout 29 days, or at least or about 30 days), the FGFR inhibitor isJNJ-42756493, and a daily dose of about 6 mg to about 12 mg (e.g., about6 mg to about 11 mg, about 10 mg, about 9 mg, about 8 mg, or about 7 mg;about 7 mg to about 12 mg, about 11 mg, about 10 mg, about 9 mg, orabout 8 mg; about 8 mg to about 12 mg, about 11 mg, about 10 mg, orabout 9 mg; about 9 mg to about 12 mg, about 11 mg, or about 10 mg;about 10 mg to about 12 mg or about 11 mg; or about 11 mg to about 12mg) of the first FGFR inhibitor is administered to the patient over thetreatment period.

In some embodiments, the treatment period is at least 21 days (e.g., atleast or about 22 days, at least or about 23 days, at least or about 24days, at least or about 25 days, at least or about 26 days, at least orabout 27 days, at least or about 28 days, at least or about 29 days, atleast or about 30 days, at least or about 31 days, at least or about 32days, at least or about 33 days, at least or about 34 days, at least orabout 35 days, at least or about 36 days, at least or about 37 days, atleast or about 38 days, at least or about 39 days, or at least or about40 days) the first FGFR is BGJ398, and a daily dose of about 50 mg toabout 125 mg (e.g., about 50 mg to about 120 mg, about 115 mg, about 110mg, about 105 mg, about 100 mg, about 95 mg, about 90 mg, about 85 mg,about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, orabout 55 mg; about 55 mg to about 120 mg, about 115 mg, about 110 mg,about 105 mg, about 100 mg, about 95 mg, about 90 mg, about 85 mg, about80 mg, about 75 mg, about 70 mg, about 65 mg, or about 60 mg; about 60mg to about 120 mg, about 115 mg, about 110 mg, about 105 mg, about 100mg, about 95 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg,about 70 mg, or about 65 mg; about 65 mg to about 120 mg, about 115 mg,about 110 mg, about 105 mg, about 100 mg, about 95 mg, about 90 mg,about 85 mg, about 80 mg, about 75 mg, or about 70 mg; about 70 mg toabout 120 mg, about 115 mg, about 110 mg, about 105 mg, about 100 mg,about 95 mg, about 90 mg, about 85 mg, about 80 mg, or about 75 mg;about 75 mg to about 120 mg, about 115 mg, about 110 mg, about 105 mg,about 100 mg, about 95 mg, about 90 mg, about 85 mg, or about 80 mg;about 80 mg to about 120 mg, about 115 mg, about 110 mg, about 105 mg,about 100 mg, about 95 mg, about 90 mg, or about 85 mg; about 85 mg toabout 120 mg, about 115 mg, about 110 mg, about 105 mg, about 100 mg,about 95 mg, or about 90 mg; about 90 mg to about 120 mg, about 115 mg,about 110 mg, about 105 mg, about 100 mg, or about 95 mg; about 95 mg toabout 120 mg, about 115 mg, about 110 mg, about 105 mg, or about 100 mg;about 100 mg to about 120 mg, about 115 mg, about 110 mg, or about 105mg; about 105 mg to about 120 mg, about 115 mg, or about 110 mg; about110 mg to about 120 mg or about 115 mg; or about 115 mg to about 120 mg)of the first FGFR inhibitor is administered to the patient over thetreatment period.

Hyperphosphatemia refers to an abnormally elevated level of phosphate inthe blood. In some embodiments, the presence of hyperphosphatemia in asubject (e.g., a patient) can be determined by measuring a level(s) ofphosphate in a biological sample including blood, serum, or plasma(e.g., peripheral blood) obtained from the patient after a particulartreatment period (e.g., any of the treatment periods described herein).Determining the phosphate level in peripheral blood can be achievedusing conventional methods known in the art (see, e.g., serum phosphatetest offered, e.g., by the Mayo Clinic Laboratories, which utilizes theRoche Phosphorus reagent (Roche Diagnostics, Inc.; the test is based onthe reaction of phosphate with ammonium molybdate to form ammoniumphosphomolybdate (without reduction)).

In certain embodiments, the serum phosphate level exhibited by a subject(e.g., a subject treated with a first FGFR inhibitor; e.g., a subjectselected in step (c) above) is at least or about 5 mg/dL, at least orabout 5.5 mg/dL, at least or about 6.0 mg/dL, at least or about 6.5mg/dL, at least or about 7.0 mg/dL, at least or about 7.5 mg/dL, atleast or about 8.0 mg/dL, at least or about 8.5 mg/dL, at least or about9.0 mg/dL, at least or about 9.5 mg/dL, at least or about 10 mg/dL, atleast or about 10.5 mg/dL, at least or about 11 mg/dL, at least or about11.5 mg/dL, at least or about 12 mg/dL, at least or about 12.5 mg/dL, atleast or about 13 mg/dL, at least or about 13.5 mg/dL, at least or about14 mg/dL, or at least or about 15 mg/dL. In some embodiments, thereference level of phosphate can be the level in a healthy subject orthe average level in a population of healthy subjects (e.g., subjectsnot having hyperphosphatemia or a subjects not at risk for developinghyperphosphatemia, such as those having a serum phosphate level of fromabout 2.0 mg/dL to about 5.0 mg/dL; e.g., from about 2.5 mg/dL to about4.5 mg/dL).

In some examples, the step (c) further includes selecting a patienthaving an elevated level of phosphate in the biological sample ascompared to a reference level of phosphate (e.g., any of the referencelevel of phosphate described herein) and one or both of: (i) acalcium-phosphate product (serum calcium in mg/dL x serum phosphate inmg/dL) of at least or about 50 mg²/dL² (e.g., at least or about 52mg²/dL², at least or about 54 mg²/dL², at least or about 56 mg²/dL², atleast or about 58 mg²/dL², at least or about 60 mg²/dL², at least orabout 62 mg²/dL², at least or about 64 mg²/dL², at least or about 66mg²/dL², at least or about 68 mg²/dL², at least or about 70 mg²/dL², atleast or about 72 mg²/dL², at least or about 74 mg²/dL², at least orabout 76 mg²/dL², at least or about 78 mg²/dL², at least or about 80mg²/dL², at least or about 82 mg²/dL², at least or about 84 mg²/dL², atleast or about 86 mg²/dL², at least or about 88 mg²/dL², at least about90 mg²/dL², at least or about 92 mg²/dL², at least or about 94 mg²/dL²,at least or about 96 mg²/dL², at least about 98 mg²/dL², or at leastabout 100 mg²/dL²) in the biological sample and (ii) a serum creatininelevel of grade 1 or greater (e.g., grade 2, grade 3) in the biologicalsample. Exemplary assays for determining the calcium level of abiological sample including blood, serum, or plasma are commerciallyavailable from BioVision Inc. (Milpitas, Calif.) and Sigma-Aldrich (St.Louis, Mo.). Exemplary assays for determining the creatinine level in abiological sample including blood, serum, or plasma are commerciallyavailable from BioVision Inc. (Milpitas, Calif.) and Diazyme (Poway,Calif.). In other embodiments, the subject exhibits a serum phosphatelevel of greater than about 7.0 mg/dL (e.g., a serum phosphate level ofgreater than 7 mg/dL lasting for more than 7 days despitephosphate-lowering therapies). In still other embodiments, the subjectexhibits a serum phosphate level of greater than about 9.0 mg/dL (e.g.,a serum phosphate level of greater than about 9.0 mg/dL for any durationdespite phosphate-lowering therapies). In still other embodiments, thesubject exhibits a serum phosphate level of greater than about 10.0mg/dL (e.g., a serum phosphate level of greater than about 10.0 mg/dLfor any duration).

In some embodiments, the patient is administered a therapeuticallyeffective amount of a phosphate binder over the treatment period.Non-limiting examples of phosphate binders include aluminum salts (e.g.,Alucaps and Basaljel), calcium carbonate (e.g., Calcichew and Titralac),calcium acetate (e.g., Lenal Ace and PhosLo), sevelamer hydrochloride(e.g., Renegel or Renvela), and lanthanum carbonate (e.g., Fosrenol). Insome embodiments, the patient is administered a therapeuticallyeffective amount of a phosphate binder each day over the treatmentperiod. The phosphate binder can be administered at a total daily doseof about 2.0 g to about 5.0 g (e.g., about 2.0 g to about 4.8 g, about4.6 g, about 4.4 g, about 4.2 g, about 4.0 g, about 3.8 g, about 3.6 g,about 3.4 g, about 3.2 g, about 3.0 g, about 2.8 g, about 2.6 g, about2.4 g, or about 2.2 g; about 2.2 g to about 5.0 g, about 4.8 g, about4.6 g, about 4.4 g, about 4.2 g, about 4.0 g, about 3.8 g, about 3.6 g,about 3.4 g, about 3.2, about 3.0 g, about 2.8 g, about 2.6 g, or about2.4 g; about 2.4 to about 5.0 g, about 4.8 g, about 4.6 g, about 4.4 g,about 4.2 g, about 4.0 g, about 3.8 g, about 3.6 g, about 3.4 g, about3.2, about 3.0 g, about 2.8 g, or about 2.6 g; about 2.6 g to about 5.0g, about 4.8 g, about 4.6 g, about 4.4 g, about 4.2 g, about 4.0 g,about 3.8 g, about 3.6 g, about 3.4 g, about 3.2, about 3.0 g, or about2.8 g; about 2.8 g to about 5.0 g, about 4.8 g, about 4.6 g, about 4.4g, about 4.2 g, about 4.0 g, about 3.8 g, about 3.6 g, about 3.4 g,about 3.2, or about 3.0 g; about 3.0 g to about 5.0 g, about 4.8 g,about 4.6 g, about 4.4 g, about 4.2 g, about 4.0 g, about 3.8 g, about3.6 g, about 3.4 g, or about 3.2 g; about 3.2 g to about 5.0 g, about4.8 g, about 4.6 g, about 4.4 g, about 4.2 g, about 4.0 g, about 3.8 g,about 3.6 g, or about 3.4 g; about 3.4 g to about 5.0 g, about 4.8 g,about 4.6 g, about 4.4 g, about 4.2 g, about 4.0 g, about 3.8 g, orabout 3.6 g; about 3.6 g to about 5.0 g, about 4.8 g, about 4.6 g, about4.4 g, about 4.2 g, about 4.0 g, or about 3.8 g; about 3.8 g to about5.0 g, about 4.8 g, about 4.6 g, about 4.4 g, about 4.2 g, or about 4.0g; about 4.0 g to about 5.0 g, about 4.8 g, about 4.6 g, about 4.4 g, orabout 4.2 g; about 4.2 g to about 5.0 g, about 4.8 g, about 4.6 g, orabout 4.4 g; about 4.4 g to about 5.0 g, about 4.8 g, or about 4.6 g;about 4.6 g to about 5.0 g or about 4.8 g; or about 4.8 g to about 5.0g) over the treatment period. In some embodiments of these methods, step(d) further includes ceasing administration of the phosphate binder tothe selected patient or instructing the selected patient to ceaseadministration of the phosphate binder. In some embodiments of thesemethods, step (d) further includes administering a decreased dose of thephosphate binder to the selected patient relative to the dose of thephosphate binder administered to the patient over the treatment period.

Also provided herein are methods of treating a FGFR-associated cancer(e.g., any of the FGFR-associated cancers described herein or known inthe art) in a patient that includes administering a therapeuticallyeffective dose of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositionincluding a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof, to a patient identified or diagnosed as having anFGFR-associated cancer over a treatment period of at least 8 days, wherethe patient is determined to have about the same or a decreased level ofphosphate in one or more biological sample(s) including blood, serum, orplasma obtained from the patient over the treatment period as comparedto a reference level of phosphate (e.g., any of the reference levels ofphosphate described herein). In some embodiments of any of thesemethods, the patient is identified or diagnosed as having aFGFR-associated cancer using any of the methods described herein orknown in the art. Some embodiments of any of these methods can furtherinclude identifying or diagnosing a subject as having a FGFR-associatedcancer using any of the methods described herein or known in the art. Insome embodiments, the treatment period of at least 8 days can be any ofthe exemplary treatment periods (or ranges of treatment periods)described herein. In some embodiments, the patient is administered adaily dose of a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof, or or a pharmaceutical composition including acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof (e.g., any of the pharmaceutical compositions described herein)over the treatment period.

In some embodiments of these methods, the patient is administered a lowdose of a phosphate binder (e.g., any of the exemplary phosphate bindersdescribed herein or known in the art) over the treatment period. In someembodiments of these methods, the phosphate binder is sevelamerhydrochloride. In some embodiments of these methods, the lose dose ofthe phosphate binder (e.g., sevelamer hydrochloride) can be a totaldaily administration of about 0.1 g to about 2.0 g (e.g., about 0.1 g toabout 1.9 g, about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g, about1.4 g, about 1.3 g, about 1.2 g, about 1.1 g, about 1.0 g, about 0.9 g,about 0.8 g, about 0.7 g, about 0.6 g, about 0.5 g, about 0.4 g, about0.3 g, or about 0.2 g; about 0.2 g to about 1.9 g, about 1.8 g., about1.7 g, about 1.6 g, about 1.5 g, about 1.4 g, about 1.3 g, about 1.2 g,about 1.1 g, about 1.0 g, about 0.9 g, about 0.8 g, about 0.7 g, about0.6 g, about 0.5 g, about 0.4 g, or about 0.3 g; about 0.3 g to about1.9 g, about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g, about 1.4 g,about 1.3 g, about 1.2 g, about 1.1 g, about 1.0 g, about 0.9 g, about0.8 g, about 0.7 g, about 0.6 g, about 0.5 g, or about 0.4 g; about 0.4g to about 1.9 g, about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g,about 1.4 g, about 1.3 g, about 1.2 g, about 1.1 g, about 1.0 g, about0.9 g, about 0.8 g, about 0.7 g, about 0.6 g, or about 0.5 g; about 0.5g to about 1.9 g, about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g,about 1.4 g, about 1.3 g, about 1.2 g, about 1.1 g, about 1.0 g, about0.9 g, about 0.8 g, about 0.7 g, or about 0.6 g; about 0.6 g to about1.9 g, about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g, about 1.4 g,about 1.3 g, about 1.2 g, about 1.1 g, about 1.0 g, about 0.9 g, about0.8 g, or about 0.7 g; about 0.7 g to about 1.9 g, about 1.8 g., about1.7 g, about 1.6 g, about 1.5 g, about 1.4 g, about 1.3 g, about 1.2 g,about 1.1 g, about 1.0 g, about 0.9 g, or about 0.8 g; about 0.8 g toabout 1.9 g, about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g, about1.4 g, about 1.3 g, about 1.2 g, about 1.1 g, about 1.0 g, or about 0.9g; about 0.9 g to about 1.9 g, about 1.8 g., about 1.7 g, about 1.6 g,about 1.5 g, about 1.4 g, about 1.3 g, about 1.2 g, about 1.1 g, orabout 1.0 g; about 1.0 g to about 1.9 g, about 1.8 g., about 1.7 g,about 1.6 g, about 1.5 g, about 1.4 g, about 1.3 g, about 1.2 g, orabout 1.1 g; about 1.1 g to about 1.9 g, about 1.8 g., about 1.7 g,about 1.6 g, about 1.5 g, about 1.4 g, about 1.3 g, or about 1.2 g;about 1.2 g to about 1.9 g, about 1.8 g., about 1.7 g, about 1.6 g,about 1.5 g, about 1.4 g, or about 1.3 g; about 1.3 g to about 1.9 g,about 1.8 g., about 1.7 g, about 1.6 g, about 1.5 g, or about 1.4 g;about 1.4 g to about 1.9 g, about 1.8 g., about 1.7 g, about 1.6 g, orabout 1.5 g; about 1.5 g to about 1.9 g, about 1.8 g., about 1.7 g, orabout 1.6 g; about 1.6 g to about 1.9 g, about 1.8 g., or about 1.7 g;about 1.7 g to about 2.0 g, about 1.9 g, or about 1.8 g; about 1.8 g toabout 2.0 g or about 1.9 g; or about 1.9 g to about 2.0 g) of thephosphate binder.

In some embodiments, the patient is determined to have about the same ora decreased level of phosphate in one or more (e.g., two, three, four,five, or six) biological sample(s) including blood, serum, or plasmaobtained from the patient at 1 day, 2 days, 3 days, 4 days, 5 days, 6days, 7 days (1 week), 8 days, 9 days, 10 days, 11 days, 12 days, 13days, 14 days (2 weeks), 15 days, 16 days, 17 days, 18 days, 19 days, 20days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60days, 61 days, 62 days, 63 days, 64 days, 65 days, 66 days, 67 days, 68days, 69 days, 70 days, 71 days, 72 days, 73 days, 74 days, 75 days, 76days, 77 days, 78 days, 79 days, 80 days, 81 days, 82 days, 83 days, 84days, 85 days, 86 days, 87 days, 88 days, 89 days, 90 days, 91 days, 92days, 93 days, 94 days, 95 days, 96 days, 97 days, 98 days, 99 days, or100 days following the start of the treatment period as compared to areference level of phosphate (e.g., any of the reference levels ofphosphate described herein).

Also provided are methods of treating a FGFR-associated cancer (e.g.,any of the FGFR-associated cancers described herein or known in the art)that include administering a therapeutically effective dose of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition including a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof (e.g., any ofthe pharmaceutical compositions described herein) to a patientidentified or diagnosed as having an FGFR-associated cancer over atreatment period (e.g., any of the treatment periods described herein),wherein the patient is not administered a phosphate binder (e.g., any ofthe phosphate binders described herein or known in the art) over orduring the treatment period. In some embodiments of any of thesemethods, the patient is identified or diagnosed as having aFGFR-associated cancer using any of the methods described herein orknown in the art. Some embodiments of any of these methods can furtherinclude identifying or diagnosing a subject as having a FGFR-associatedcancer using any of the methods described herein or known in the art. Insome embodiments, the treatment period can be any of the exemplarytreatment periods described herein or any of the exemplary ranges oftreatment periods described herein. In some embodiments, the patient isadministered a daily dose of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition including a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof (e.g., any of the pharmaceuticalcompositions described herein) over the treatment period.

Also provided herein are methods of treating a FGFR-associated cancer(e.g., any FGFR-associated cancer described herein or known in the art)in a patient that include administering a therapeutically effective doseof a compound of Formula I or pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition including a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof(e.g., any of the pharmaceutical compositions described herein) to apatient identified or diagnosed as having an FGFR-associated cancer overa treatment period (e.g., any of the treatment periods describedherein), wherein the patient is further administered a low dose of aphosphate binder (e.g., any of the phosphate binders described herein,e.g., sevelamer hydrochloride) (e.g., any of the low doses of aphosphate binder described herein) over or over at least a part of thetreatment period. Some embodiments of any of these methods can furtherinclude identifying or diagnosing a subject as having a FGFR-associatedcancer using any of the methods described herein or known in the art. Insome embodiments, the treatment period can be any of the exemplarytreatment periods described herein or any of the exemplary ranges oftreatment periods described herein. In some embodiments, the patient isadministered a daily dose of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition including a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof (e.g., any of the pharmaceuticalcompositions described herein) over the treatment period.

Also provided are methods of treating a patient having a FGFR-associatedcancer (e.g., any of the FGFR-associated cancers described herein orknown in the art) that include administering a therapeutically effectivedose of a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition including a compound ofFormula I of a pharmaceutically acceptable salt or solvate thereof(e.g., any of the pharmaceutical compositions described herein) to apatient identified or diagnosed as having an FGFR-associated cancer overa treatment period (e.g., any of the treatment periods describedherein), where the patient does not experience or is less likely toexperience one or more (e.g., two, three, four, five, six, seven, eight,or nine) of soft tissue calcification, stomatitis, dry mouth, nailchanges, fatigue, asthenia, anorexia, malaise, and muscle aches over thetreatment period or after the treatment period (e.g., as compared to apatient or a population of patients having the same FGFR-associatedcancer and administered a therapeutically effective dose of a FGFRinhibitor that is not a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositionincluding a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof, over the same treatment period). Some embodiments ofany of these methods can further include identifying or diagnosing asubject as having a FGFR-associated cancer using any of the methodsdescribed herein or known in the art. In some embodiments, the treatmentperiod can be any of the exemplary treatment periods described herein orany of the exemplary ranges of treatment periods described herein. Insome embodiments, the patient is administered a daily dose of a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof,or a pharmaceutical composition including a compound of Formula I or apharmaceutically acceptable salt or solvate thereof (e.g., any of thepharmaceutical compositions described herein) over the treatment period.

In some embodiments of these methods, the patient is not administered aphosphate binder (e.g., any of the phosphate binders described herein orknown in the art) during the treatment period. In such methods, thepatient can be, e.g., less likely to experience one or more (e.g., two,three, four, five, six, seven, eight, or nine) of soft tissuecalcification, stomatitis, dry mouth, nail changes, fatigue, asthenia,anorexia, malaise, and muscle aches over the treatment period or afterthe treatment period (e.g., as compared to a patient or a population ofpatients having the same FGFR-associated cancer and administered atherapeutically effective dose of a FGFR inhibitor that is not acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition including a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof, and is notadministered a phosphate binder, over the same treatment period).

In some embodiments of these methods, the patient is administered a lowdose of a phosphate binder (e.g., any of the phosphate binders describedherein, e.g., sevelamer hydrochloride) (e.g., any of the exemplary lowdoses of a phosphate binder described herein). In such methods, thepatient can be, e.g., less likely to experience one or more (e.g., two,three, four, five, six, seven, eight, or nine) of soft tissuecalcification, stomatitis, dry mouth, nail changes, fatigue, asthenia,anorexia, malaise, and muscle aches over the treatment period or afterthe treatment period (e.g., as compared to a patient or a population ofpatients having the same FGFR-associated cancer and administered atherapeutically effective dose of a FGFR inhibitor that is not acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition including a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof, and isadministered the same low dose of phosphate binder, over the sametreatment period).

The level of soft tissue calcification can be detected/determined in apatient by a medical professional using, e.g., ultrasound, radiography,computed tomography, and magnetic resonance imaging. The level ofstomatitis, dry mouth, nail changes, fatigue, asthenia, anorexia,malaise, and muscle aches in a patient can be determined by a medicalprofessional through the physical examination of the patient and/orinterviewing the patient (e.g., using a survey).

In some embodiments, the patient is less likely to experience one ormore (e.g., two, three, four, five, six, seven, eight, or nine) of softtissue calcification, stomatitis, dry mouth, nail changes, fatigue,asthenia, anorexia, malaise, and muscle aches over the treatment periodor after the treatment period (e.g., as compared to a patient or apopulation of patients having the same FGFR-associated cancer andadministered a therapeutically effective dose of a FGFR inhibitor thatis not a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition including a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, andis administered the same low dose of phosphate binder, over the sametreatment period).

The phrase “effective amount” means an amount of compound that, whenadministered to a patient in need of such treatment, is sufficient to(i) treat a particular disease, condition, or disorder mediated byFGFR1, FGFR2 FGFR3 and/or FGFR4, (ii) attenuate, ameliorate, oreliminate one or more symptoms of the particular disease, condition, ordisorder, or (iii) delay the onset of one or more symptoms of theparticular disease, condition, or disorder described herein. The amountof a compound of Formula I that will correspond to such an amount willvary depending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight) of the patientin need of treatment, but can nevertheless be routinely determined byone skilled in the art.

When employed as pharmaceuticals, the compounds provided herein can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable

Also provided herein pharmaceutical compositions which contain, as theactive ingredient, a compound as provided herein or a pharmaceuticallyacceptable salt or solvate thereof, in combination with one or morepharmaceutically acceptable carriers (excipients). In some embodiments,the composition is suitable for topical administration. In making thecompositions provided herein, the active ingredient is typically mixedwith an excipient, diluted by an excipient or enclosed within such acarrier in the form of, for example, a capsule, sachet, paper, or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders. In oneembodiment, the composition is formulated for oral administration. Inone embodiment, the composition is formulated as a tablet or capsule.

The compositions comprising a compound provided herein or apharmaceutically acceptable salt or solvate thereof can be formulated ina unit dosage form, each dosage containing from about 5 to about 1,000mg (1 g), more usually about 100 mg to about 500 mg, of the activeingredient. The term “unit dosage form” refers to physically discreteunits suitable as unitary dosages for human subjects and other patients,each unit containing a predetermined quantity of active material (i.e.,a compound for Formula I as provided herein) calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

In some embodiments, the compositions provided herein contain from about5 mg to about 50 mg of the active ingredient. One having ordinary skillin the art will appreciate that this embodies compounds or compositionscontaining about 5 mg to about 10 mg, about 10 mg to about 15 mg, about15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40mg to about 45 mg, or about 45 mg to about 50 mg of the activeingredient.

In some embodiments, the compositions provided herein contain from about50 mg to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compounds orcompositions containing about 50 mg to about 100 mg, about 100 mg toabout 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about450 mg to about 500 mg of the active ingredient.

In some embodiments, the compositions provided herein contain from about500 mg to about 1,000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compounds orcompositions containing about 500 mg to about 550 mg, about 550 mg toabout 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg toabout 950 mg, or about 950 mg to about 1,000 mg of the activeingredient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like. In some embodiments, the activecompound is administered at a dosage of from about 0.001 mg/Kg to about500 mg/Kg (e.g., from about 0.001 mg/Kg to about 200 mg/Kg; from about0.01 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg;from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about50 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kgto about 5 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about0.01 mg/Kg to about 0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg;from about 0.1 mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about150 mg/Kg; from about 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kgto about 50 mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about0.1 mg/Kg to about 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; fromabout 0.1 mg/Kg to about 0.5 mg/Kg).

Provided herein are pharmaceutical kits useful, for example, in thetreatment of FGFR-associated diseases or disorders, such as cancer,which include one or more containers containing a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundprovided herein. Such kits can further include, if desired, one or moreof various conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trialsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

EXAMPLES

The following examples illustrate the invention.

Synthetic Examples

Synthesis of Synthetic Intermediates

Abbreviations

ACN Acetonitrile bis(pinacolato)diboron4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) Boct-butoxycarbonyl Cu(OAc)₂ Copper (II) Acetate DCM Dichloromethane DIPEAN,N-Diisopropylethylamine DMF N,N-Dimethylformamide Dppf 1,1′-bis(diphenylphosphanyl) ferrocene Eq equivalent/equivalents Et₂O Diethylether EtOAc Ethyl Acetate EtOH Ethanol GFF paper or GF/F paper Whatmanglass microfiber filter paper H hour/hours HATU2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate iPrOH Isopropanol KOAc Potassium Acetate MeOHMethanol Min minute/minutes MsCl methansulfonyl chloride NBSN-Bromosuccinimide Pd(OAc)₂ Palladium (II) Acetate Pd(PPh₃)₄Tetrakis(triphenylphosphine)palladium (0) PdCl₂(dppf)•CH₂Cl₂1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex TEA Triethylamine TFA Trifluoroacetic acid THFtetrahydrofuran TLC thin layer chromatography X-Phosdicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine

Synthesis of Synthetic Intermediates

Intermediate S1

(2R,5R)-tert-butyl5-methyl-2-(((methylsulfonyl)ox)methyl)morpholine-4-carboxylate

A cold (0° C.) solution of (2R,5R)-tert-butyl2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate (275 mg, 1.19 mmol)and DIPEA (312 μL, 1.78 mmol) in DCM (6 mL) was treated with MsCl (110μL, 1.43 mmol). The resulting mixture was stirred overnight at ambienttemperature. The mixture was partitioned between saturated NaHCO_(3(aq))(30 mL) and DCM (20 mL), and the aqueous extracts were washed withadditional DCM (2×10 mL). The combined organic extracts were washed withbrine (10 mL), dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum affording the title compound (367 mg, 99%yield). This material was of sufficient purity to be used directlywithout further purification.

The following intermediates shown in Table S1 were prepared accordingthe method used for the synthesis of Intermediate S1 using theappropriate chiral hydroxymethyl-(morpholine)carboxylate startingmaterials. The reaction progression in each was followed by TLC (50%Hexanes/EtOAc, KMnO₄ stain) and reaction times were adjusted asnecessary.

TABLE S1 Intermediate Structure Name S2

tert-butyl (2S,5R)-5-methyl-2-(((methylsulfonyl)oxy)methyl)morpholine-4- carboxylate S3

tert-butyl (S)-5,5-dimethyl-2-(((methylsulfonyl)oxy)methyl)morpholine-4- carboxylate S4

tert-butyl (R)-5,5-dimethyl-2-(((methylsulfonyl)oxy)methyl)morpholine-4- carboxylate S5

tert-butyl (R)-6-(((methylsulfonyl)oxy)methyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate

Intermediate S6

(1-cyanocyclopropyl)methyl methanesulfonate

A solution of 1-(hydroxymethyl)cyclopropanecarbonitrile (1.14 g, 11.7mmol) in DCM (24 mL) was treated with TEA (3.50 mL, 25.8 mmol). Theresulting reaction mixture was cooled to 0° C., treated dropwise withMsCl (1.37 mL, 17.6 mmol) and stirred for 1 h at 0° C. The reactionmixture was stirred at ambient temperature for an additional 2 h beforebeing diluted with additional DCM (100 mL) and washed with brine (25mL). The organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated under vacuum to afford the title compound(2.057 g, 100% yield). This material was of sufficient purity to be useddirectly without further purification. 1H NMR (400 MHz, DMSO-d6) δ 4.27(s, 2H), 3.23 (s, 3H), 1.42-1.38 (m, 2H), 1.21-1.18 (m, 2H).

Intermediate P1

tert-butyl(2R,5R)-5-methyl-2-((4-(4,4,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(276 mg, 1.42 mmol), (2R,5R)-tert-butyl5-methyl-2-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate(Intermediate S1; 367 mg, 1.19 mmol), and Cs₂CO_(3(s)) (966 mg, 2.97mmol) was suspended in DMF (5.93 mL) and stirred for 1 day at ambienttemperature. The mixture was partitioned between EtOAc (100 mL) and H₂O(50 mL). The organic extracts were separated and then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum. Thecrude residue was purified by silica chromatography (0-100%EtOAc/Hexanes) to afford the title compound (483 mg, 100% yield). MS(apci) m/z=408.2 (M+H).

The following intermediates shown in Table P1 were prepared accordingthe method used for the synthesis of Intermediate P1, tert-butyl(2R,5R)-5-methyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate,using the appropriate chiralmethanesulfonoxy-methyl-morpholine-4-carboxylate starting materials(Intermediates S2-S5 from Table S1). All compounds were purified using amethod similar to that used for purifying Intermediate P1 utilizing theappropriate gradient for the silica chromatography.

TABLE P1 MS (apci) Intermediate Structure Name m/z P2

tert-butyl (2S,5R)- 5-methyl-2-((4- (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazol-1- 408.3 (M + H) yl)methyl)morpholine-4-carboxylate P3

tert-butyl (S)-5,5- dimethyl-2-((4- (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazol-1- yl)methyl)morpholine- 422.2 (M + H)4-carboxylate P4

tert-butyl (R)-5,5- dimethyl-2-((4- (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazol-1- yl)methyl)morpholine- 422.2 (M + H)4-carboxylate P5

tert-butyl (R)-6- ((4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-1- yl)methyl)-7-oxa-4- azaspiro[2.5]octane- 420.2 (M + H)4-carboxylate

Intermediate P6

1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carbonitrile

A solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.52 g,7.83 mmol) in DMA (31 mL) was treated with 1-cyanocyclopropyl)methylmethanesulfonate (Intermediate S6; 1.99 g, 11.4 mmol), Cs₂CO_(3(s))(3.83 g, 11.8 mmol) and 4A molecular sieves (250 mg). The resultingsuspension was stirred for 16 h at 100° C. After cooling to ambienttemperature, the reaction mixture was filtered, and the solids collectedwere rinsed with EtOAc (50 mL). The filtrate was diluted with toluene(150 mL) and concentrated under vacuum. The resulting crude residue wasazeotroped with toluene (150 mL) several times to remove most of the DMAand subsequently purified by silica chromatography (5-75% Hexanes/EtOAcas the gradient eluent) to afford the title compound (1.38 g, 65%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (s, 1H), 7.65 (s, 1H), 4.28 (s,2H), 1.33-1.23 (m, 16H).

Intermediate P7

4,4,4-trifluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-ol

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(500 mg, 2.58 mmol), 2-(2,2,2-trifluoroethyl)oxirane (390 mg, 3.09mmol), and Cs₂CO_(3(s)) (1.68 g, 5.15 mmol) was suspended in DMF (2.58mL) and stirred overnight at 80° C. The mixture was partitioned betweenEtOAc (50 mL) and H₂O (25 mL). The organic extracts were separated thendried over anhydrous Na₂SO_(4(s)) filtered and concentrated under vacuumto afford the title compound (825 mg, 100% yield). MS (apci) m/z=321.1(M+H). This material was of sufficient purity to be used directlywithout further purification.

Intermediate P8

2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrileStep 1: Preparation of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile

A solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.11 g,26.3 mmol) in DMF (50 mL) was treated with bromoacetonitrile (2.20 mL,31.6 mmol) and K₂CO_(3(s)) (5.46 g, 39.5 mmol). The resulting suspensionwas stirred for 24 h at 100° C. The reaction mixture was cooled toambient temperature, diluted with water (100 mL) then extracted withEtOAc (3×250 mL). The combined organic extracts were washed with water(3×50 mL) and brine (50 mL) then dried over anhydrous Na₂SO_(4(s)).Following filtration, the organic extracts were concentrated undervacuum then purified by silica chromatography (10-60% Hexanes/EtOAc asthe gradient eluent) to afford the title compound (2.42 g, 39% yield).¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.71 (s, 1H), 5.49 (s, 2H),1.25 (s, 12H).

Step 2: Preparation of2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile

A cold (0° C.) solution of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile(2.42 g, 10.4 mmol) in THF (26 mL) was treated with iodomethane (1.94mL, 31.1 mmol) then drop-wise with sodium bis(trimethylsilyl)amide (22.8mL, 22.8 mmol). The resulting mixture was stirred 1 h at 0° C. beforequenching with the addition of saturated NH₄Cl_((aq)) (25 mL). Atambient temperature the reaction mixture was then partitioned betweenEtOAc (250 mL) and water (100 mL). The organic extracts were washedagain with water (50 mL) and brine (50 mL), then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated under vacuum. The crude residuewas purified by silica chromatography (5-50%, Hexanes/EtOAc as thegradient eluent) to afford the title compound (1.35 g, 50% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 8.20 (s, 1H), 7.75 (s, 1H), 1.97 (s, 6H), 1.26(s, 12H).

Intermediate P9

2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.16 g, 11.1 mmol) and Cs₂CO_(3(s)) (3.81 g, 11.7 mmol) in2,2-dimethyloxirane (3 mL, 33.6 mmol) was stirred overnight at 100° C.The reaction mixture was filtered through GFF paper and the filtrate wasconcentrated under vacuum to afford the title compound (2.48 g, 84%yield). This material was of sufficient purity to be used directlywithout further purification. ¹H NMR (CDCl3) δ 7.81 (s, 1H), 7.69 (s, 1H

Intermediate Y1

tert-butyl 4-(5-aminopyrazin-2-yl)-1H-pyrazole-1-carboxylate

A mixture of 2-amino-5-bromopyrazine (100 mg, 0.575 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(338 mg, 1.15 mmol), PdCl₂(dppf).CH₂Cl₂ (47.3 mg, 0.0575 mmol),K₂CO_(3(s)) (238 mg, 1.72 mmol) was suspended in a mixture of dioxane(5.75 mL) and water (1.15 mL). The mixture was sparged with Ar_((g)),then sealed and stirred for 4 h at 90° C. After cooling to ambienttemperature, the reaction mixture was diluted with EtOAc, filtered thenconcentrated under vacuum. The crude residue was purified by silicachromatography (70-100% EtOAc in Hexanes as the eluent) to afford thetitle compound (84 mg, 56% yield). MS (apci) m/z=162.1 (desBoc M+H).

The following 4-(5-aminopyrazin-2-yl)-1H-pyrazole intermediates, shownin Table Y1, were prepared in a manner similar to the method used forthe synthesis of Intermediate Y1, using the appropriate arylboronatestarting materials (commercially available or synthesized according toExamples provided herein), excess K₂CO_(3(s)) (0.1-0.2 equivalents),0.1-0.2 M in 5:1 dioxane:water and temperatures between 85-90° C.Reaction progression in each was followed by LCMS and reactions timeswere adjusted as necessary. All compounds were purified by silicachromatography as in Intermediate Y1 utilizing the appropriate eluent.

TABLE Y1 MS (apci) Intermediate Structure Name m/z Y9

(2R,5R)-tert-butyl 2- ((4-(5-aminopyrazin- 2-yl)-1H-pyrazol-1-yl)methyl)-5- methylmorpholine-4- carboxylate 275.1 [(M-Boc) + H)] Y10

(2S,5R)-tert-butyl 2- ((4-(5-aminopyrazin- 2-yl)-1H-pyrazol-1-yl)methyl)-5- methylmorpholine-4- carboxylate 275.1 [(M-Boc) + H)] Y11

tert-butyl (S)-2-((4-(5- aminopyrazin-2-yl)- 1H-pyrazol-1-yl)methyl)-5,5- dimethylmorpholine- 4-carboxylate 389.2 (M + H) Y12

tert-butyl (R)-2-((4-(5- aminopyrazin-2-yl)- 1H-pyrazol-1-yl)methyl)-5,5- dimethylmorpholine- 4-carboxylate 389.2 (M + H) Y13

tert-butyl (R)-6-((4-(5- aminopyrazin-2-yl)- 1H-pyrazol-1-yl)methyl)-7-oxa-4- azaspiro[2.5]octane-4- carboxylate 387.2 (M + H)

Intermediate Y2

5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine

A solution of 2-amino-5-bromopyrazine (5.7 g, 33 mmol) in 4:1dioxane:water (300 mL) was treated with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(7.2 g, 34 mmol), PdCl₂(dppf).CH₂Cl₂ (1.3 g, 1.6 mmol), K₂CO_(3(s)) (14g, 98 mmol). The mixture was sparged with Ar_((g)), then sealed andstirred for 16 h at 100° C. After cooling to ambient temperature, thereaction mixture was diluted with 4:1 DCM/iPrOH (500 mL), and theresulting solution was extracted with water (2×100 mL). The organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum. The resulting crude residue was purified bysilica chromatography (1-30% DCM/MeOH as the gradient eluent) to affordthe title compound (63.4 mg, 63% yield). MS (apci) m/z=176.1 (M+H).

Intermediate Y3

5-(1-isopropyl-1H-pyrazol-4-yl)pyrazin-2-amine

A mixture of 2-amino-5-bromopyrazine (0.505 g, 2.90 mmol),1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.822 g, 3.48 mmol), Pd(PPh₃)₄ (0.168 g, 0.145 mmol), 2M Na₂CO_(3(aq))(3.05 mL, 6.09 mmol) in dioxane (9 mL) was stirred overnight at 90° C.After cooling to ambient temperature, the reaction mixture was dilutedwith DCM then extracted with water and brine. The organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered then concentrated undervacuum. The resulting crude residue was purified by silicachromatography to afford the title compound (0.415 g, 70% yield). MS(apci) m/z=204.1 (M+H).

The following 4-(5-aminopyrazin-2-yl)-1H-pyrazole intermediates, shownin Table Y3, were prepared according the method used for the synthesisof Intermediate Y3 using the appropriate arylboronate starting materials(commercially available or prepared as described herein). Reactionprogression in each was followed by LCMS and reaction time was adjustedas necessary. All compounds were purified by silica chromatographyaccording to the method for the isolation of Intermediate Y3 utilizingthe appropriate eluent.

TABLE Y3 Intermediate MS (apci) # Structure Name m/z Y4

5-(1-isobutyl-1H- pyrazol-4- yl)pyrazin-2-amine 218.1 (M + H) Y6

5-(1- (cyclopropylmethyl)- 1H-pyrazol-4- yl)pyrazin-2-amine 216.1 (M +H) Y7

5-(1-cyclobutyl- 1H-pyrazol-4- yl)pyrazin-2-amine 216.1 (M + H) Y8

5-(1-(2- morpholinoethyl)- 1H-pyrazol-4- yl)pyrazin-2-amine 275.1 (M +H) Y17

1-(4-(5- aminopyrazin-2- yl)-1H-pyrazol-1- yl)-2- methylpropan-2-ol234.2 (M + H)

Intermediate Y5

5-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazin-2-amine

A mixture of 2-amino-5-bromopyrazine (90.6 mg, 0.521 mmol),1-(pentan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(194 mg, 0.573 mmol), PdCl₂(dppf).CH₂Cl₂ (42.84 mg, 0.0521 mmol),K₂CO_(3(s)) (216 mg, 1.56 mmol) was suspended in a mixture of dioxane(5.21 mL), and water (1.04 mL). The mixture was sparged with Ar_((g)),then sealed and stirred overnight at 90° C. After cooling to ambienttemperature, the reaction mixture was diluted with DCM and water. Theorganic extracts were washed with water and brine then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum. Theresulting crude residue was purified by silica chromatography (70-100%EtOAc in Hexanes as the eluent) to afford the title compound (40 mg, 33%yield). MS (apci) m/z=232.1 (M+H).

Intermediate Y14

1-((4-(5-aminopyrazin-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carbonitrile

A solution of1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropanecarbonitrile(Intermediate P6; 560.0 mg, 2.050 mmol) in 4:1 dioxane:water (10 mL) wastreated with 2-amino-5-bromopyrazine (356.7 mg, 2.050 mmol), Pd(PPh₃)₄(236.9 mg, 0.2050 mmol), K₂CO_(3(s)) (850.1 mg, 6.151 mmol). The mixturewas sparged with Ar_((g)), then sealed and stirred for 16 h at 100° C.After cooling to ambient temperature, the reaction mixture was dilutedwith 4:1 DCM:iPrOH (200 mL) and the resulting solution was extractedwith water (2×50 mL). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated under vacuum. The resultingcrude residue was purified by silica chromatography (1-30% DCM/MeOH asthe gradient eluent) to afford the title compound (246.6 mg, 51% yield).MS (apci) m/z=241.1 (M+H).

Intermediate Y15

1-(4-(5-aminopyrazin-2-yl)-1H-pyrazol-1-yl)-4,4,4-trifluorobutan-2-ol

The title compound was prepared (83.2 mg, 23% yield) according to themethod described for Intermediate Y14, using4,4,4-trifluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-ol(Intermediate P7) in place of1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropanecarbonitrile(Intermediate P6). MS (apci) m/z=288.0 (M+H).

Intermediate Y16

2-(4-(5-aminopyrazin-2-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile

A solution of 2-amino-5-bromopyrazine (258.9 mg, 1.488 mmol) in 4:1dioxane:water (10 mL) was treated with1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropanecarbonitrile(Intermediate P8; 560.0 mg, 2.050 mmol), PdCl₂(dppf).CH₂Cl₂ (122.4 mg,0.1488 mmol), K₂CO_(3(s)) (616.9 mg, 4.464 mmol). The mixture wassparged with Ar_((g)), then sealed and stirred for 16 h at 100° C. Aftercooling to ambient temperature, the reaction mixture was diluted with4:1 DCM:iPrOH (250 mL) and the resulting solution was extracted withwater (2×50 mL). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated under vacuum. The resultingcrude residue was purified by C18 reverse phase chromatography (5-95%water/ACN with 0.1% TFA as the gradient eluent) to afford the titlecompound as a TFA salt. The TFA salt was dissolved in 4:1 DCM:iPrOH (100mL) and extracted with saturated NaHCO_(3(aq)) (1×25 mL). The organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum to cleanly afford the title compound (77 mg,23% yield). MS (apci) m/z=229.1 (M+H).

Intermediate Y18

2-(4-(5- aminopyrazin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol

The title compound was prepared (97.2 mg, 23% yield) according to themethod described for Intermediate Y16, using2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-olin place of1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropanecarbonitrile(Intermediate P9). MS (apci) m/z=234.1 (M+H).

Intermediate Y19

tert-butyl4-(4-(5-aminopyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of 2-amino-5-bromopyrazine (5.0 g, 28.7 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(11.9 g, 31.6 mmol), Pd(PPh₃)₄ (3.32 g, 2.87 mmol), 2M Na₂CO_(3(aq))(35.9 mL, 71.8 mmol) in dioxane (57.5 mL) was purged with N_(2(g)) for 6min then sealed and stirred for 16 h at 90° C. After cooling to ambienttemperature, the reaction mixture was diluted with EtOAc (300 mL) andwashed with water (2×80 mL). The combined organic extracts were driedover anhydrous MgSO_(4(s)), filtered and concentrated under vacuum. Theresulting crude residue was precipitated from hot ACN (X mL) to providepure title compound (6.35 g). Mother liquor was concentrated undervacuum and the residue obtained was purified by flash chromatography onsilica gel (Redi Sep 220 g) eluting with 5-60% acetone/DCM (15CV) toprovide additional title compound (3.17 g; 96% total yield). MS (apci)m/z=245.1 [(M-Boc)+H]. MS data are for the purified forms of batch landbatch 2.

Intermediate Y20

5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine

A solution of 2-amino-5-bromopyrazine 1.03 g, 5.95 mmol) in 4:1dioxane:water (20 mL) was treated with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.30 g, 6.25 mmol), PdCl₂(dppf).CH₂Cl₂ (0.490 g, 0.595 mmol),K₂CO_(3(s)) (2.47 g, 17.9 mmol). The mixture was sparged with Ar_((g)),then sealed and stirred for 16 h at 100° C. After cooling to ambienttemperature, the reaction mixture was diluted with 4:1 DCM:iPrOH (250mL) and the resulting solution was extracted with water (2×50 mL). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum. The resulting crude residue was purified bysilica chromatography (1-30% DCM/MeOH as the gradient eluent) to affordthe title compound (845.5 mg, 82% yield). MS (apci) m/z=175.1 (M+H).

Intermediate Y21

tert-butyl4-(4-(6-aminopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

The title compound was prepared (1.12 g, 85% yield) according to themethod described for Intermediate Y21, using tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylatein place of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole anda step wise gradient eluent system of 5-60% DCM/EtOAc then 1-25%DCM/MeOH in the silica chromatography. MS (apci) m/z=344.1 (M+H).

Intermediate L1

tert-butyl 4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazole-1-carboxylate

A solution of tert-butyl4-(5-aminopyrazin-2-yl)-1H-pyrazole-1-carboxylate (Intermediate Y1; 84mg, 0.32 mmol) in CHCl₃ (3.2 mL) was treated with pyridine (29 μL, 0.35mmol) and the resulting solution was cooled to 0° C. Br₂ (17 μL, 0.34mmol) was added dropwise to the solution and the resulting reactionmixture was stirred at 0° C. for 30 min. The reaction mixture was thenstirred at ambient temperature for 2 h prior to quenching with 10%Na₂S₂O_(3(aq)). The resulting biphasic mixture was extracted with DCM.The organic extracts were dried over anhydrous Na₂SO_(4(s)), filteredand concentrated under vacuum. The resulting crude residue was purifiedby silica chromatography (30-100% EtOAc in Hexanes as the gradienteluent) to afford the title compound (69 mg, 63% yield). MS (apci)m/z=242.0 [(M-Boc)+H+2], 240 [(M-Boc)+H], with Br pattern.

The following intermediates shown in Table L1 were prepared accordingthe method used for the synthesis of Intermediate L1. Reactionprogression in each was followed by LCMS and reaction time was adjustedas necessary. All compounds were purified by silica chromatographyaccording the method used for purifying Intermediate L1 using theappropriate gradient eluent.

TABLE L1 Intermediate # Structure Name MS (apci) m/z L5

3-bromo-5-(1- (pentan-3-yl)-1H- pyrazol-4- yl)pyrazin-2-amine 312.0([(M + H) + 2] 310 (M + H) (with bromine pattern) L19

tert-butyl 4-(4-(5- amino-6- bromopyrazin-2- yl)-1H-pyrazol-1-yl)piperidine-1- carboxylate 369.0 ([(des(tBu)M + H) + 2] 367(des(tBu)M + H) (with bromine pattern)

Intermediate L2

3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine

A cold (0° C.) solution of 5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine(Intermediate Y2; 0.210 g, 1.20 mmol) and pyridine (0.107 mL, 1.32 mmol)in CHCl₃ (10 mL) was treated a solution of Br₂ (0.422 g, 2.64 mmol) inCHCl₃ (4 mL). The resulting reaction mixture was maintained at 0° C. for5 min and then allowed to stir at ambient temperature for 2 h. Thereaction mixture was then diluted with DCM (50 mL) prior to quenchingwith saturated Na₂S₂O_(3(aq)) (20 mL). The resulting biphasic mixturewas separated, the organic extracts were reserved and the aqueousextracts were washed with DCM (50 mL). The combined organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered and concentrated undervacuum. The resulting crude residue was purified by silicachromatography (1:1 EtOAc/Hexanes as the eluent) to afford the titlecompound (0.266 g, 87% yield). MS (apci) m/z=256.0 [(M+H)+2], 254.0(M+H), with Br pattern.

Intermediate L3

3-bromo-5-(1-isopropyl-1H-pyrazol-4-yl)pyrazin-2-amine

A cold (0° C.) solution of5-(1-isopropyl-1H-pyrazol-4-yl)pyrazin-2-amine (Intermediate Y3; 0.365g, 1.80 mmol) and pyridine (0.160 mL, 1.98 mmol) in CHCl₃ (12 mL) wastreated with Br₂ (0.0971 mL, 1.89 mmol). The reaction mixture wasstirred overnight at ambient temperature then diluted with DCM andextracted with saturated Na₂S₂O_(3(aq)). The organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum. The resulting crude residue was purified bysilica chromatography to afford the title compound (0.247 g, 49% yield).MS (apci) m/z=282.0 (M+H), 284.0 [[(M+H)+2]](bromine pattern).

The following intermediates shown in Table L3 were prepared accordingthe method used for the synthesis of Intermediate L3 in CHCl₃ (0.1-0.15M). Reaction progression in each was followed by LCMS and reaction timewas adjusted as necessary. All compounds were purified by silicachromatography according the method used for isolating Intermediate L3using the appropriate gradient eluent.

TABLE L3 Intermediate # Structure Name MS (apci) m/z L4

3-bromo-5-(1-isobutyl- 1H-pyrazol-4- yl)pyrazin-2-amine 296.0 (M + H),298.0 [(M + H) + 2] (with bromine pattern) L6

3-bromo-5-(1- (cyclopropylmethyl)- 1H-pyrazol-4- yl)pyrazin-2-amine294.0 (M + H), 296.0 [[(M + H) + 2]] (with bromine pattern) L7

3-bromo-5-(1- cyclobutyl-1H-pyrazol- 4-yl)pyrazin-2-amine 296.0 [[(M +H) + 2]], 294.0 (M + H) (with bromine pattern) L8

3-bromo-5-(1-(2- morpholinoethyl)-1H- pyrazol-4-yl)pyrazin-2- amine354.9 [(M + H) + 2], 353.0 (M + H) (with bromine pattern) L17

1-(4-(5-amino-6- bromopyrazin-2-yl)-1H- pyrazol-1-yl)-2-methylpropan-2-ol 314.09 [[(M + H) + 2]], 312.0 (M + H) (with brominepattern)

Intermediate L10

tert-butyl(2S,5R)-2-((4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5-methylmorpholine-4-carboxylate

A solution of (2S,5R)-tert-butyl2-((4-(5-aminopyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5-methylmorpholine-4-carboxylate(Intermediate Y10; 150 mg, 0.401 mmol) and pyridine (35.61 μL, 0.441mmol) in CHCl₃ (4.01 mL) was cooled to 0° C., stirred for 30 min, thentreated dropwise with Br₂ (21.552 μL, 0.421 mmol). The reaction mixture,then was stirred overnight at ambient temperature prior to quenchingwith 10% Na₂S₂O_(3(aq)). The resulting biphasic mixture was extractedwith DCM (3x). The organic extracts were washed with water (2x) andbrine then dried over anhydrous MgSO_(4(s)), filtered and concentratedunder vacuum. The resulting crude residue was purified by silicachromatography (60-100% EtOAc/Hexanes as the gradient eluent) to affordthe title compound (50 mg, 28% yield). MS (apci) m/z=455.0 [(M+H)+2],453 (M+H), with Br pattern.

The following intermediates shown in Table L10 were prepared accordingthe method used for the synthesis of Intermediate L10 in CHCl₃ (0.1-0.2M), from the appropriate starting materials prepared as describedherein. Reaction progression was followed by LCMS and reaction time wasadjusted as necessary. All compounds were purified by silicachromatography as in Intermediate L10 using the appropriate gradienteluent.

TABLE L10 Intermediate # Structure Name MS (apci) m/z L9 ^(a)

tert-butyl (2R,5R)-2- ((4-(5-amino-6- bromopyrazin-2-yl)- 1H-pyrazol-1-yl)methyl)-5- methylmorpholine-4- carboxylate 455.0 [(M + H) + 2] 453(M + H) L11

tert-butyl (S)-2-((4- (5-amino-6- bromopyrazin-2-yl)- 1H-pyrazol-1-yl)methyl)-5,5- dimethylmorpholine- 4-carboxylate 467.0 (M+),  469.1(M + 2) L12

tert-butyl (R)-2-((4- (5-amino-6- bromopyrazin-2-yl)- 1H-pyrazol-1-yl)methyl)-5,5- dimethylmorpholine- 4-carboxylate 467.1 (M+),  469.1(M + 2) L13

tert-butyl (R)-6-((4- (5-amino-6- bromopyrazin-2-yl)- 1H-pyrazol-1-yl)methyl)-7-oxa-4- azaspiro[2.5]octane- 4-carboxylate 465.1 (M+), 467.1 (M + 2) ^(a) Additional Br₂ (0.5 equivalents) was necessary

Intermediate L16

2-(4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile

A solution of2-(4-(5-aminopyrazin-2-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile(Intermediate Y16; 77.0 mg, 0.337 mmol) in CHCl₃ (3.4 mL) was treatedwith pyridine (30.1 μL, 0.371 mmol). The resulting solution was cooledto 0° C. and then treated with Br₂ (18.2 μL, 0.354 mmol). The reactionmixture was stirred 16 h at ambient temperature prior to quenching with10% Na₂S₂O_(3(aq)) (10 mL). The resulting biphasic mixture was dilutedwith 4:1 DCM:iPrOH (50 mL) and washed with water (2×25 mL). The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum. The resulting crude residue was purified bysilica chromatography (1-25% DCM/MeOH as the gradient eluent) to affordthe title compound (79.3 mg, 77% yield). MS (apci) m/z=307.0 [(M+H)+2],308.9 (M+H), with Br pattern.

The following intermediates shown in Table L16 were prepared accordingthe method used for the synthesis of Intermediate L16 from theappropriate starting materials prepared as described herein. Reactionprogression in each was followed by LCMS and reaction time was adjustedas necessary. All compounds were purified by silica chromatographyaccording to the method for isolating Intermediate L16 using theappropriate gradient eluent.

TABLE L16 Intermediate MS (apci) # Structure Name m/z L14

1-((4-(5-amino- 6-bromopyrazin- 2-yl)-1H-pyrazol-1-yl)methyl)cyclopropane- 1-carbonitrile 320.9 [(M + H) + 2] 319.0 (M + H)(with bromine pattern) L15

1-(4-(5-amino-6- bromopyrazin-2- yl)-1H-pyrazol- 1-yl)-4,4,4-trifluorobutan-2-ol 367.9 [(M + H) + 2] 366 (M + H) (with brominepattern) L18

2-(4-(5-amino-6- bromopyrazin-2- yl)-1H-pyrazol- 1-yl)-2-methylpropan-1-ol 314.0 [(M + H) + 2] 312 (M + H) (with bromine pattern)

Intermediate L20

3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine

A solution of 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (IntermediateY20; 845.5 mg, 4.854 mmol) in CHCl₃ (25 mL) was treated with pyridine(431.8 μL, 5.339 mmol). The resulting solution was cooled to 0° C. thentreated with Br₂ (261.1 μL, 5.096 mmol). The reaction mixture wasstirred 16 h at ambient temperature prior to quenching with 10%Na₂S₂O_(3(aq)) (10 mL). The resulting biphasic mixture was extractedwith CHCl₃ (2×100 mL). The combined organic extracts washed with 10%Na₂S₂O_(3(aq)) (25 mL), then dried over anhydrous Na₂SO_(4(s)), filteredand concentrated under vacuum. The resulting crude residue was purifiedby silica chromatography (1-25% DCM/MeOH as the gradient eluent) toafford the title compound (500.5 mg, 41% yield). MS (apci) m/z=254.9[(M+H)+2], 252.9 (M+H), with Br pattern.

Intermediate L21

tert-butyl4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

The title compound was prepared (622.4 mg, 45% yield) according to themethod described for Intermediate L20, using tert-butyl4-(4-(6-aminopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate Y21) in place of5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine with excess bromine/pyridine(1.6 eq each) and a gradient eluent system of 10-90% DCM/EtOAc in thesilica chromatography. MS (apci) m/z=424 [(M+H)+2], 422.0 (M+H) with Brpattern.

Intermediate L22

3-bromo-5-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-amine

Step 1: Tert-butyl4-(4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate L19; 2.0 g, 4.7 mmol) was treated with TFA (5 mL) andstirred at ambient temperature. After 30 minutes, the TFA was removed invacuo and the residue was treated with 4N HCl in dioxane (50 mL) to formthe HCl salt. The resulting mixture was concentrated in vacuo and theresidue was dried under high vacuum to a constant weight to provide3-bromo-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-aminedihydrochloride (2.1 g, 5.3 mmol, 112% yield) as a white solid. MS(apci) m/z=325 [(M+H)+2], 323.0 (M+H) with Br pattern.

Step 2: 3-Bromo-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl) pyrazin-2-aminedihydrochloride (1.9 g, 4.797 mmol) was dissolved in DMF (100 mL) andtreated with K₂CO₃ (2.652 g, 19.19 mmol). The mixture was cooled to 0°C. and treated dropwise with 1-bromo-2-methoxyethane (0.4508 ml, 4.797mmol) while maintaining the internal temperature at 0° C., and thenallowed to warm to ambient temperature while stirring for 72 hours. Thereaction mixture was poured into ice water (1.0 L) and extracted with 5%IPA in DCM. The organics were washed with brine, then, dried over MgSO₄,filtered and concentrated in vacuo. The crude product was purified byflash chromatography (2-15% MeOH in DCM with 2% NH₄OH) to provide thetitle compound (1.2 g, 3.147 mmol, 65.62% yield) as an off white solid.MS (apci) m/z=383.1 [(M+H)+2], 381 (M+H) with Br pattern.

Intermediate X2

6-chloro-2-(3-methoxy-5-(trifluoromethoxy)phenyl)pyridazin-3 (2H)-one

A mixture of 6-chloropyridazin-3(2H)-one (0.125 g, 0.958 mmol),(3-methoxy-5-(trifluoromethoxy)phenyl)boronic acid (0.339 g, 1.44 mmol),Cu(OAc)₂ (0.0348 g, 0.192 mmol) and pyridine (0.155 mL, 1.92 mmol) inDCM (9.58 mL) was stirred overnight at ambient temperature. The mixturewas diluted with DCM and washed with water and brine then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum. Theresulting crude residue was purified by silica chromatography to affordthe title compound (307 mg, 82% yield). MS (apci) m/z=323.0 [(M+H)+2],321.0 (M+H) with Cl pattern.

The following intermediates, shown in Table X2 were prepared accordingthe method used for the synthesis of Intermediate X2 using theappropriate arylboronic acid starting materials. Reaction progression ineach was followed by LCMS and reaction time was adjusted as necessary.All compounds were purified by silica chromatography according to themethod used to isolate Intermediate X2.

TABLE X2 Intermediate Structure Name Spectral Data X1 ^(a)

6-chloro-2-(3- methoxyphenyl)pyridazin- 3(2H)-one ¹H NMR (DMSO-d₆) δ7.60 (d, 1H), 7.38 (t, 1H), 7.12 (d, 1H), 7.07 (m, 2H), 7.00 (m, 1H),3.75 (s, 3H) X5

6-chloro-2-(3- isopropoxy-5- methoxyphenyl)pyridazin- 3(2H)-one MS(apci) m/z = 297.1 [(M + H) + 2], 295.0 (M + H) with Cl pattern X7*

6-chloro-2-(o- tolyl)pyridazin-3(2H)- one ¹H NMR (CDCl₃) δ 7.30 (m, 4H),7.04 (d, 1H), 2.19 (s, 3H) ^(a) used 10 times the amount of Cu(OAc)₂used for preparing Intermediate X2 but otherwise the procedure was asdescribed for Intermediate X2

Intermediate X3

6-chloro-2-(3-ethoxy-5-(trifluoromethoxy)phenyl)pyridazin-3 (2H)-one

6-chloro-2-(3-ethoxy-5-(trifluoromethoxy)phenyl)pyridazin-3(2H)-one wasmade according to the procedure of Intermediate X2 substituting(3-methoxy-5-(trifluoromethoxy)phenyl)boronic acid for(3-ethoxy-5-(trifluoromethoxy)phenyl)boronic acid.

Intermediate X4

6-chloro-2-(3-methoxy-5-(trifluoromethyl)phenyl)pyridazin-3 (2H)-one

6-chloro-2-(3-methoxy-5-(trifluoromethyl)phenyl)pyridazin-3(2H)-one wasmade according to the procedure for Intermediate X2, substituting(3-methoxy-5-(trifluoromethoxy)phenyl)boronic acid for(3-methoxy-5-(trifluoromethyl)phenyl)boronic acid.

Intermediate X6

6-chloro-2-(2-chloro-3-methoxyphenyl)pyridazin-3 (2H)-one

6-chloro-2-(2-chloro-3-methoxyphenyl)pyridazin-3 (2H)-one was madeaccording to the procedure for Intermediate X2, substituting(3-methoxy-5-(trifluoromethoxy)phenyl)boronic acid for(2-chloro-3-methoxyphenyl)boronic acid.

Intermediate X8

6-chloro-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of 6-chloropyridazin-3(2H)-one (506.5 mg, 3.880 mmol) in DCM(38 mL) was treated with 3,5-dimethoxyphenylboronic acid (776.8 mg,4.268 mmol), Cu(OAc)₂ (1410 mg, 7.760 mmol), and pyridine (627.7 μL,7.760 mmol). The resulting mixture was stirred open to the atmospherefor 60 h at ambient temperature. The reaction mixture was filtered, andthe filtrate was concentrated under vacuum. The resulting crude residuewas purified by silica chromatography (5-60% DCM/EtOAc as the gradienteluent) to afford the title compound (560 mg, 54% yield). MS (apci)m/z=269.0 [(M+H)+2], 267.0 (M+H), with Cl pattern.

The following intermediates shown in Table X8 were prepared accordingthe method used for the synthesis of Intermediate X8 using theappropriate arylboronic acid starting materials. Reaction progression ineach was followed by LCMS and reaction time was adjusted as necessary.All compounds were purified by silica chromatography according to themethod used to isolate Intermediate X8.

TABLE X8 Intermediate Structure Name Spectral Data X9

6-chloro-2-(3,4- dimethoxyphenyl)pyridazin- 3(2H)-one MS (apci) m/z =269.0 [(M + H) + 2], 267.0 (M + H), with Cl pattern X16

methyl 3-(3-chloro- 6-oxopyridazin- 1(6H)-yl)benzoate ¹H NMR (400 MHz,DMSO-d₆) δ 8.15-8.14 (m, 1H), 8.03-8.00 (m, 1H), 7.89-7.86 (m, 1H),7.69-7.65 (m, 2H), 7.21- 7.18 (d, 1H), 3.89 (s, 3H)

Intermediate X10

6-chloro-2-(5-methoxy-2-methylphenyl)pyridazin-3(2H)-one

A solution of 6-chloropyridazin-3(2H)-one (811.1 mg, 6.214 mmol) in DCM(31 mL) was treated with (5-methoxy-2-methylphenyl)boronic acid (1031mg, 6.214 mmol), Cu(OAc)₂ (2257 mg, 12.43 mmol), and pyridine (1005 μL,12.43 mmol). The resulting mixture was stirred open to the atmospherefor 16 h at ambient temperature. The reaction mixture was filtered, andthe filtrate was concentrated under vacuum. The resulting crude residuewas purified by C18 reverse phase chromatography (5-95% water/ACN with0.1% TFA as the gradient eluent) to afford the title compound as a TFAsalt. The TFA salt was dissolved in 4:1 DCM:iPrOH (100 mL) and extractedwith saturated NaHCO_(3(aq)) (1×25 mL). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated under vacuumcleanly affording the title compound (251 mg, 16% yield). MS (apci)m/z=253.0 [(M+H)+2], 251.0 (M+H) with Cl pattern.

Intermediate X11

6-chloro-2-(1,5-dimethyl-1H-indazol-4-yl)pyridazin-3(2H)-one

The title compound was prepared (52 mg, 12% yield) according to themethod described for Intermediate X10, using1,5-dimethyl-1H-indazole-4-boronic acid in place of(5-methoxy-2-methylphenyl)boronic acid. MS (apci) m/z=277.0 [(M+H)+2],275.0 (M+H) with Cl pattern.

Intermediate X12

3-(3-chloro-6-oxopyridazin-1(6H)-yl)-5-methoxybenzonitrile Step 1:Preparation of (3-cyano-5-methoxyphenyl)boronic acid

A mixture of3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(0.450 g, 1.74 mmol), sodium periodate (1.11 g, 5.21 mmol) and 1 MCH₃COONH_(4(aq)) (3.47 mL, 3.47 mmol) in acetone (7 mL) was stirred 3 hat ambient temperature. The reaction was quenched with 4 M HCl_((aq)) (1mL) then stirred for 20 min. The mixture was then diluted with EtOAc andextracted with water and brine, then dried over anhydrous Na₂SO_(4(s)),filtered and concentrated under vacuum to afford the title compound(0.300 g, 98% yield).

Step 2: Preparation of3-(3-chloro-6-oxopyridazin-1(6H)-yl)-5-methoxybenzonitrile

A mixture of 6-chloropyridazin-3(2H)-one (0.200 g, 1.53 mmol),(3-cyano-5-methoxyphenyl)boronic acid (0.298 g, 1.69 mmol), Cu(OAc)₂(0.0557 g, 0.306 mmol) and pyridine (0.273 mL, 3.37 mmol) in DCM (9.58mL) was stirred overnight at ambient temperature. The mixture was thendiluted with DCM and extracted with water and brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum. Theresulting crude residue was purified by silica chromatography to affordthe title compound (197 mg, 49% yield). ¹H NMR (CDCl₃) δ 7.60 (t, 1H),7.49 (t, 1H), 7.28 (d, 1H), 7.18 (m, 1H), 7.40 (d, 1H), 3.88 (s, 3H).

Intermediate X13

6-chloro-2-(2-fluoro-3,5-dimethoxyphenyl)pyridazin-3 (2H)-one Step 1:Preparation of (2-fluoro-3,5-dimethoxyphenyl)hydrazine

A cold (0° C.) solution of 2-fluoro-3,5-dimethoxyaniline (1.00 g, 5.84mmol) in 12.5 M HCl_((aq)) (7.01 mL, 87.6 mmol) was slowly treated withNaNO_(2(s)) (0.605 g, 8.76 mmol) then stirred for 1 h at ambienttemperature. The resulting reaction mixture then was treated withSnCl₂.H₂O (2.64 g, 11.7 mmol), and stirred overnight at ambienttemperature. The reaction mixture then was filtered, washing the solidswith water. The filtrate was cooled to 0° C. and slowly basified withthe addition of NaOH pellets. The resulting mixture was extracted withethyl acetate (5×250 mL), and the combined organic extracts were washedwith brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum to afford the title compound (724 mg, 67%yield). MS (apci) m/z=187.1 (M+H). This material was used withoutpurification in the subsequent step.

Step 2: Preparation of1-(2-fluoro-3,5-dimethoxyphenyl)-1,2-dihydropyridazine-3,6-dione

A solution of furan-2,5-dione (0.381 g, 3.89 mmol) and(2-fluoro-3,5-dimethoxyphenyl)hydrazine (from step 1; 0.724 g, 3.89mmol) in EtOH (absolute; 19.4 mL) was heated for 1 day at 95° C. thentreated with 6 N HCl in iPrOH (2.5 mL). After 3 h the reaction mixturewas concentrated under vacuum. The resulting residue was suspended inDCM and the insoluble material was removed by filtration. The filtratethen was concentrated under vacuum, and the residue was purified bysilica chromatography (0-100% EtOAc/hexanes as the gradient eluent) tocleanly afford the title compound (140.5 mg, 14% yield). MS (apci)m/z=267.0 (M+H).

Step 3: Preparation of6-chloro-2-(2-fluoro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of1-(2-fluoro-3,5-dimethoxyphenyl)-1,2-dihydropyridazine-3,6-dione (140mg, 0.526 mmol) in POCl₃ (490 μL, 5.26 mmol) was heated at 85° C. for 1h. The reaction mixture was then concentrated under vacuum, and theresulting residue was partitioned between EtOAc and saturatedNaHCO_(3(aq)). The phases were separated and treated independently. Theaqueous extracts were washed with EtOAc (2x) and the organic extractsfrom the wash were combined with the original organic extract. Thecombined organic extracts were washed with brine then dried overanhydrous Na₂SO_(4(s)), filtered and the concentrated under vacuum. Theresulting residue was purified by silica chromatography (0-100%EtOAc/hexanes as the gradient eluent) to afford the title compound (94mg, 63% yield). MS (apci) m/z=285.0 (M+H).

Intermediate X14

6-chloro-2-(2-fluoro-5-methoxyphenyl)pyridazin-3 (2H)-one Step 1:Preparation of1-(2-fluoro-5-methoxyphenyl)-1,2-dihydropyridazine-3,6-dione

A solution of furan-2,5-dione (255 mg, 2.60 mmol) and(2-fluoro-3,5-dimethoxyphenyl)hydrazine hydrochloride (500 mg, 2.60mmol) in EtOH (absolute; 152 mL, 2.60 mmol) was heated for 1 day at 95°C. The reaction mixture was concentrated under vacuum, and the resultingresidue was purified by silica chromatography (0-100% EtOAc/hexanes asthe gradient eluent) to cleanly afford the title compound (300 mg, 49%yield). MS (apci) m/z=237.0 (M+H).

Step 2: Preparation of6-chloro-2-(2-fluoro-5-methoxyphenyl)pyridazin-3(2H)-one

A solution of1-(2-fluoro-5-methoxyphenyl)-1,2-dihydropyridazine-3,6-dione (90 mg,0.38 mmol) in POCl₃ (355 μL, 3.8 mmol) was heated at 85° C. for 1 h. Thereaction mixture was then concentrated under vacuum, and the resultingresidue was partitioned between EtOAc and saturated NaHCO_(3(aq)). Thephases were separated and treated independently. The aqueous extractswere washed with EtOAc (2x), and the organic extracts from the wash werecombined with the original organic extract. The combined organicextracts were washed with brine then dried over anhydrous Na₂SO_(4(s)),filtered and the concentrated under vacuum. The resulting residue waspurified by silica chromatography (0-100% EtOAc/hexanes as the gradienteluent) to afford the title compound (38 mg, 39% yield). MS (apci)m/z=255.0 (M+H).

Intermediate X15

6-chloro-2-(2-chloro-3,5-dimethoxyphenyl)pyridazin-3 (2H)-one

A cold (0° C.) solution of6-chloro-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one (Intermediate X8;0.357 g, 1.34 mmol) in ACN (13.4 mL) was treated with SO₂Cl₂ (0.109 mL,1.34 mmol) and stirred for 20 min. The resulting mixture was quenchedwith the addition of saturated NaHCO_(3(aq)). The resulting biphasicmixture was extracted with EtOAc. The organic extracts were washedsuccessively with water and brine then dried over anhydrousNa₂SO_(4(s)), filtered and the concentrated under vacuum. The resultingcrude residue was purified by silica chromatography to afford the titlecompound (310 mg, 77% yield). ¹H NMR (CDCl₃) δ 7.29 (d, 1H), 7.04 (d,1H), 6.58 (m, 2H), 3.90 (s, 3H), 3.81 (s, 3H).

Intermediate O2

6-chloro-2-(2-chloro-3,5-dimethoxyphenyl)pyridazin-3 (2H)-one

A cold (0° C.) solution of6-chloro-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one (2.496 g, 9.360mmol) in ACN (93.60 mL, 9.360 mmol) was treated with sulfuryl dichloride(1.484 mL, 18.25 mmol) and stirred for 1 hr. The resulting mixture wasquenched with the addition of saturated NaHCO_(3(aq)). The resultingbiphasic mixture was extracted with DCM. The organic extracts werewashed successively with water and brine then dried over anhydrousNa₂SO_(4(s)), filtered and then concentrated in vacuo to afford thetitle compound (3.1 g, 99% yield). This material was of sufficientpurity to be used directly without further purification. ¹H NMR (CDCl₃)δ 7.29 (d, 1H), 7.04 (d, 1H), 6.65 (s, 1H), 3.94 (s, 6H).

Intermediate X17

6-chloro-4-methylpyridazin-3(2H)-one Step 1: Preparation of6-chloro-3-methoxy-4-methylpyridazine

A solution of 2,2,6,6-tetramethylpiperidine (12.9 ml, 76.1 mmol) in THF(100 mL) was sparged with N_(2(g)) then cooled to −78° C. The −78° C.solution was treated slowly with 2.5 M n-butyllithium in hexane (30.4mL, 76.1 mmol) then warmed to 0° C. and stirred for 1 h. The resultingreaction mixture was cooled to −78° C. then treated with a 0.46 Msolution of 3-Chloro-6-methoxypyridazine in THF (75 mL, 34.6 mmol).After stirring at −78° C. for 1 h, the reaction mixture was treated withiodomethane (4.74 mL, 76.1 mmol), and stirred for an additional 30 minat −78° C. The reaction mixture was quenched with saturated NH₄Cl_((aq))(50 mL), warmed to ambient temperature, diluted with water (50 mL) andextracted with EtOAc (2×250 mL). The combined organic extracts werewashed with brine (1×50 mL), dried over anhydrous Na₂SO_(4(s)), filteredand concentrated under vacuum to afford the title compound (3.31 g, 60%yield). MS (apci) m/z=159.0 (M+H).

Step 2: Preparation of 6-chloro-4-methylpyridazin-3(2H)-one

A solution of 6-chloro-3-methoxy-4-methylpyridazine (3.31 g, 20.9 mmol)in 4:1 dioxane:water (100 mL) was treated with 12.0 M HCl_((aq)) (1.91mL, 23.0 mmol) and stirred for 60 h at 60° C. The reaction mixture wasconcentrated under vacuum, and the resulting crude residue was purifiedby silica chromatography (1-30% DCM/MeOH with 2% NH₄OH as the gradienteluent) to afford the title compound (2.99 g, 99% yield). ¹H NMR (400MHz, DMSO-d₆) δ 13.03 (s, 1H), 7.44 (s, 1H), 2.05 (s, 3H).

Intermediate X18

6-chloro-2-(3,5-dimethoxyphenyl)-4-methylpyridazin-3 (2H)-one

A solution of 6-chloro-4-methylpyridazin-3-ol (Intermediate X17; 500 mg,3.46 mmol) in DCM (20.3 mL) and pyridine (1 mL, 3.46 mmol) was treatedwith (3,5-dimethoxyphenyl)boronic acid (1.26 g, 6.92 mmol), Cu(OAc)₂(1.26 g, 6.92 mmol), and pyridine 1-oxide (1.32 g, 13.8 mmol). Theresulting mixture was stirred open to the atmosphere overnight atambient temperature. The reaction mixture was diluted with DCM (100 mL)and filtered. The filtrate was washed with water (2×30 mL), and theorganics were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum. The crude residue was precipitated from MeOHto cleanly afford the title compound (780 mg, 80%). MS (apci) m/z=281.1(M+H), 283.0 [(M+H)+2] (with Cl pattern).

Intermediate X19

methyl 3-(3-chloro-5-methyl-6-oxopyridazin-1(6H)-yl)-4-methylbenzoate

A solution of 6-chloro-4-methylpyridazin-3-ol (Intermediate X17; 0.50 g,3.4 mmol) in DCM (20 mL) was treated with(5-(methoxycarbonyl)-2-methylphenyl)boronic acid (1.0 g, 5.2 mmol),Cu(OAc)₂ (1.2 g, 6.9 mmol), pyridine 1-oxide (327 mg, 3.44 mmol) andpyridine (1.1 g, 14 mmol). The resulting mixture was stirred at ambienttemperature open to the atmosphere for one overnight. The reactionmixture was diluted with DCM (100 mL) and washed with water (2×30 mL).The organic extracts were dried over anhydrous Na₂SO_(4(s)), filteredand concentrated under vacuum. The crude residue was purified by silicagel flash chromatography (2-55% EtOAc/hexane as the gradient eluent) toafford the title compound (2.99 g, 99% yield). MS (apci) m/z=293.0(M+H), 295.0 [(M+H)+2] (with Cl pattern).

Intermediate X20

4-bromo-6-chloropyridazin-3 (2H)-one

A solution of 6-chloropyridazin-3-ol (5.01 g, 38.38 mmol), KBr (13.70 g,115.1 mmol), and KOAc (5.650 g, 57.57 mmol) in water (80 mL) was stirredfor 15 min then treated with Br₂ (5.90 mL, 115 mmol). The resultingmixture was stirred under an atmosphere of N_(2(g)) for 2 h at 90° C.After cooling to ambient temperature the reaction mixture was quenchedwith 10% Na₂S₂O_(3(aq)) (100 mL). The resulting biphasic suspension wasfiltered, and the filter cake was successively rinsed with water (100mL) then 10% Na₂S₂O_(3(aq)) (100 mL). The solid filter cake was driedunder high vacuum for 16 h to cleanly afford the title compound (6.14 g,76% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (s, 1H), 8.20 (s, 1H).

Intermediate X21

4-bromo-6-chloro-2-(3,5-dimethoxyphenyl)pyridazin-3 (2H)-one

A mixture of 4-bromo-6-chloropyridazin-3(2H)-one (Intermediate X20;0.504 g, 2.41 mmol), (3,5-dimethoxyphenyl)boronic acid (0.482 g, 2.65mmol), Cu(OAc)₂ (0.0874 g, 0.481 mmol) and pyridine (0.389 mL, 4.81mmol) in DCM (24.1 mL) was stirred overnight at ambient temperature Themixture was then diluted with DCM and extracted with water. The organicextracts were washed with brine, then dried aver anhydrous Na₂SO_(4(s)),filtered and concentrated under vacuum. The resulting crude residue waspurified by silica chromatography to afford the title compound (0.574 g,69% yield). ¹H NMR (CDCl₃) δ 7.69 (s, 1H), 6.73 (d, 2H), 6.51 (t, 1H),3.81 (s, 6H).

Intermediate X22

6-chloro-4-cyclobutyl-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A cold (0° C.) solution of4-bromo-6-chloro-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Intermediate X21; 413.7 mg, 1.197 mmol) in THF (12 mL) was treated with0.5 M cyclobutylmagnesium chloride hexane (3591 μL, 1.796 mmol) andstirred for 1 h at 0° C. The reaction was quenched with the addition ofwater (25 mL) and the volatiles were removed under vacuum. The remainingaqueous mixture was diluted with EtOAc (100 mL) and washed successivelywith water (2×25 mL) and brine (25 mL). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum. Theresulting residue was purified by silica chromatography (5-60%Hexanes/EtOAc as the gradient eluent) to afford the title compound (283mg, 72% yield). MS (apci) m/z=311.0 [(M+H)+2], 309.0 (M+H) with Clpattern.

The following intermediates shown in Table X22 were prepared accordingto the method used for the synthesis of Intermediate X22 using theappropriate alkylmagnesium halide starting materials and4-bromo-6-chloro-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one. Reactionprogression in each was followed by LCMS and reaction time was adjustedas necessary. All compounds were purified using a method similar to thatused to isolate Intermediate X22 utilizing the appropriate gradienteluent.

TABLE X22 Intermediate Structure Name MS (apci) m/z X23

6-chloro-2-(3,5- dimethoxyphenyl)-4- isopropylpyridazin-3(2H)- one 311.0[(M + H) + 2], 309.0 (M + H) with Cl pattern X24

6-chloro-4-cyclopropyl-2- (3,5- dimethoxyphenyl)pyridazin- 3(2H)-one309.0 [(M + H) + 2], 307.0 (M + H) with Cl pattern

Intermediate X25

6-chloro-2-(3,5-dimethoxyphenyl)-4-isobutylpyridazin-3 (2H)-one

A cold (0° C.) solution of4-bromo-6-chloro-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Intermediate X21; 0.150 g, 0.434 mmol) in THF (2.89 mL) was treatedwith 2 M isobutylmagnesium bromide in Et₂O (0.434 mL, 0.868 mmol). Thereaction was stirred overnight at ambient temperature and then worked upwith EtOAc and water. The organics were washed with brine, then driedover anhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum. Theresulting residue was purified by silica chromatography to afford thetitle compound (0.035 g, 25% yield).

The following intermediates, shown in Table X25 were prepared accordingthe method used for the synthesis of Intermediate X25 using theappropriate alkylmagnesium halide starting materials and4-bromo-6-chloro-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one. Allcompounds were purified by silica chromatography utilizing theappropriate gradient.

TABLE X25 Intermediate Structure Name X26

6-chloro-2-(3,5-dimethoxyphenyl)-4- ethylpyridazin-3(2H)-one X27

6-chloro-2-(3,5-dimethoxyphenyl)-4- propylpyridazin-3(2H)-one

Intermediate X28

6-chloro-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one

Sulfuryl chloride (0.152 mL, 1.88 mmol) was added to6-chloro-2-(3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one(Intermediate X18; 0.264 g, 0.940 mmol) in ACN (6.27 mL) at 0° C. Thiswas then stirred at room temp for 20 min. The mixture was then quenchedwith saturated aqueous Na₂CO₃. The mixture was partitioned between EtOAcand water. The combined organic layers were washed with water and brine,dried over Na₂SO₄, and concentrated. The residue was purified on asilica column using Hexanes:EtOAc (10-90%) to give6-chloro-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one(0.198 g, 0.566 mmol, 60.2% yield) MS (apci) m/z=349.0 (M+H).

Intermediate X29

6-chloro-2-(3-methylquinolin-7-yl)pyridazin-3 (2H)-one

Step 1: Preparation of (3-methylquinolin-7-yl)boronic acid: A solutionof 7-bromo-3-methylquinoline (258 mg, 1.16 mmol),5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (656 mg, 2.90 mmol),PdCl2(dppf).dcm (47.4 mg, 0.0581 mmol), and KOAc (342 mg, 3.49 mmol) indioxane (5809 μL, 1.16 mmol) was sparged with N_(2(g)) for 5 min atambient temperature and then heated at 90° C. overnight. After coolingto ambient temperature, the reaction mixture was partitioned betweenEtOAc and water. The combined organic extracts were washed with brine,dried over anhydrous Na₂SO_(4(s)), filtered and concentrated undervacuum to afford the title compound with higher than expected mass, butassumed with quantitative yield (217 mg, 100% yield). MS (apci)m/z=188.1 (M+H).

Step 2: Preparation of:6-chloro-2-(3-methylquinolin-7-yl)pyridazin-3(2H)-one: A mixture of6-chloropyridazin-3(2H)-one (0.140 g, 1.07 mmol),(3-methylquinolin-7-yl)boronic acid, (0.221 g, 1.18 mmol), Cu(OAc)2(0.0390 g, 0.215 mmol) and pyridine (0.191 ml, 2.36 mmol) in DCM (10.7mL, 1.07 mmol) was stirred at room temperature overnight. The reactionmixture was partitioned between EtOAc and water. The organic extractswere washed with brine, then dried over anhydrous Na₂SO_(4(s)), filteredand concentrated under vacuum. The resulting residue was purified bysilica chromatography to afford the title compound (25 mg, 8.6% yield).MS (apci) m/z=274.0 [(M+H)+2], 272.0 (M+H) with Cl pattern.

Intermediate X30

Methyl 3-(3-chloro-5-methyl-6-oxopyridazin-1 (6H)-yl)-4-methylbenzoate

A solution of 6-chloro-4-methylpyridazin-3-ol (0.5 g, 3.5 mmol) indichloromethane (20 mL, 3.4 mmol) was treated with(5-(methoxycarbonyl)-2-methylphenyl)boronic acid (1 g, 5.15 mmol),copper(II) acetate (1.25 g, 6.87 mmol), pyridine 1-oxide (33 mg, 3.44mmol), and pyridine (1.1 g, 13.75 mmol). The resulting mixture wasstirred overnight at RT. The mixture was diluted with DCM (100 mL) andwashed with water (2×30 mL). The organic layer was separated, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby flash chromatography on silica gel (Redi Sep 80 g) eluting with 2-55%EtOAc/hexane to provide methyl3-(3-chloro-5-methyl-6-oxopyridazin-1(6H)-yl)-4-methylbenzoate (430 mg,43% yield) as a solid. LCMS (APCI+) m/z 293.0 (M+1); retentiontime=4.086 min.

Intermediate R1

2-(3-methoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one

A solution of 6-chloro-2-(3-methoxyphenyl)pyridazin-3(2H)-one(Intermediate X1; 104 mg, 0.439 mmol) in dioxane (6 mL) was treated withbis(pinacolato)diboron (123 mg, 0.483 mmol), Pd(OAc)₂ (10.8 mg, 0.0483mmol), X-Phos (34.6 mg, 0.0725 mmol), and KOAc (129 mg, 1.32 mmol). Themixture was sparged with Ar_((g)), then sealed and stirred for 16 h at100° C. After cooling to ambient temperature, the reaction mixture wasfiltered, and the filter cake was washed with EtOAc (50 mL). Thefiltrate was concentrated under vacuum to afford the title compound (157mg, 109% crude yield). This material was used directly without furtherpurification.

Intermediate R2

2-(3-methoxy-5-(trifluoromethoxy)phenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one

A mixture of6-chloro-2-(3-methoxy-5-(trifluoromethoxy)phenyl)pyridazin-3(2H)-one(Intermediate X2; 0.253 g, 0.789 mmol), bis(pinacolato)diboron (0.220 g,0.868 mmol), Pd(OAc)₂ (0.0177 g, 0.0789 mmol), X-Phos (0.0564 g, 0.118mmol), and KOAc (0.232 g, 2.37 mmol) in dioxane (2.63 mL) was spargedwith Ar_((g)) for 5 min at ambient temperature then stirred for 1 h at100° C. After cooling to ambient temperature, the reaction mixture waspartitioned between EtOAc and water. The organic extracts were washedwith brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum to afford the title compound (320 mg, 98%yield). MS (apci) m/z=287.0 (M-B(OR)₂+H). This material was ofsufficient purity to be used directly without further purification.

The following intermediates shown in Table R2 were prepared accordingthe method used for the synthesis of Intermediate R2 using theappropriate 6-chloro-2-(Aryl)pyridazin-3(2H)-one starting materials(Intermediates X3-X7, X11-X12, X15). Reaction progression for each wasfollowed by LCMS and reaction time was adjusted as necessary.

TABLE R2 MS (apci) Intermediate Structure Name m/z R3

2-(3-ethoxy-5- (trifluoromethoxy)phenyl)- 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one 301.1 (M—B(OR)₂ + H) R4

2-(3-methoxy-5- (trifluoromethyl)phenyl)- 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one 271.1 (M—B(OR)₂ + H) R5

2-(3-isopropoxy-5- methoxyphenyl)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one 261.1 (M—B(OR)₂ + H) R6

2-(2-chloro-3- methoxyphenyl)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one 237 (M—B(OR)₂ + H) R12

3-methoxy-5-(6-oxo-3- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridazin-1(6H)- yl)benzonitrile 226.1 (M—B(OR)₂ + H) R15

2-(2-chloro-3,5- dimethoxyphenyl)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one 267 (M—B(OR)₂ + H) R16

2-(2,6-dichloro-3,5- dimethoxyphenyl)-4- methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)pyridazin-3(2H)-one 315(M—B(OR)₂ + H) R17

2-(2,6-dichloro-3,5- dimethoxyphenyl)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one 301 (M—B(OR)₂ + H)

Intermediate R7

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(o-tolyl)pyridazin-3(2H)-one

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(o-tolyl)pyridazin-3(2H)-one was made according the procedure of Intermediate R2,substituting Intermediate X2 with Intermediate X7.

Intermediate R8

2-(3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one

A solution of 6-chloro-2-(3,5-dimethoxyphenyl)pyridazin-3 (2H)-one(Intermediate X8; 47.9 mg, 0.180 mmol) in dioxane (1.8 mL) was treatedwith bis(pinacolato)diboron (50.2 mg, 0.198 mmol), Pd(OAc)₂ (4.03 mg,0.0180 mmol), X-Phos (12.8 mg, 0.0269 mmol), and KOAc (52.9 mg, 0.539mmol). The mixture was sparged with Ar_((g)), then sealed and stirredfor 16 h at 100° C. After cooling to ambient temperature, the reactionmixture was diluted with 4:1 DCM:iPrOH (25 mL) then extracted with water(2×10 mL). The organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated under vacuum to afford the title compound (64mg, 99% yield). MS (apci) m/z=233.1 (desB(OR)₂ M+H). This material wasof sufficient purity to be used directly without further purification.

The following intermediates shown in Table R8, were prepared accordingthe method used for the synthesis of Intermediate R8 using theappropriate 6-chloro-2-(Aryl)pyridazin-3(2H)-one starting materials(Intermediates X9, X10). Reaction progression in each was followed byLCMS and reaction time was adjusted as necessary.

TABLE R8 Inter- mediate Structure Name MS (apci) m/z = R9

2-(3,4-dimethoxyphenyl)- 6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one 277.0 (B(OH)₂ M+), 233.0 (M—B(OR)₂ + H) R10

2-(5-methoxy-2- methylphenyl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one 261.0 (B(OH)₂ M+), 217.1(M—B(OR)₂ + H)

Intermediate R13

2-(2-fluoro-3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one

A solution of6-chloro-2-(2-fluoro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Intermediate X13; 94 mg, 0.33 mmol) in dioxane (1.2 mL) was treatedwith bis(pinacolato)diboron (0.17 g, 0.66 mmol), Pd(OAc)₂ (7.4 mg, 0.033mmol), X-Phos (23.6 mg, 0.050 mmol), and KOAc (97 mg, 0.99 mmol). Themixture was sparged with Ar_((g)), then sealed and stirred for 3 h at90° C. After cooling to ambient temperature, the reaction mixture waspartitioned between EtOAc and water. The organic extracts were reservedand the aqueous extracts were independently washed with EtOAc (3×). Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated under vacuum to afford the title compound(124.2 mg, 75% yield). MS (apci) m/z=251.1 (desB(OR)₂ M+H). Thismaterial was of sufficient purity to be used directly without furtherpurification.

Intermediate R14

2-(2-fluoro-5-methoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one

The title compound was prepared (116.9 mg, 50% yield) according to themethod described for Intermediate R14, using6-chloro-2-(2-fluoro-5-methoxyphenyl)pyridazin-3(2H)-one (IntermediateX14) in place of6-chloro-2-(2-fluoro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Intermediate X13). MS (apci) m/z=221.1 (desB(OR)₂ M+H). This materialwas of sufficient purity to be used directly without furtherpurification.

Intermediate R18

2-(3,5-dimethoxyphenyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one

A solution of6-chloro-2-(3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one(Intermediate X18; 199.4 mg, 0.7103 mmol) in dioxane (7.1 mL) wastreated with bis(pinacolato)diboron (198.4 mg, 0.7814 mmol), Pd(OAc)₂(15.95 mg, 0.07103 mmol), X-Phos (50.80 mg, 0.1066 mmol), and KOAc(209.1 mg, 2.131 mmol). The mixture was sparged with Ar_((g)), thensealed and stirred for 1 h at 100° C. After cooling to ambienttemperature, the reaction mixture was diluted with 4:1 DCM:iPrOH (50 mL)then extracted with water (2×25 mL). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum toafford the title compound (264 mg, 100% yield). MS (apci) m/z=291.1(B(OH)₂ M+H), 247.1 (desB(OR)₂ M+H). This material was of sufficientpurity to be used directly without further purification.

Intermediate R19

methyl4-methyl-3-(5-methyl-6-oxo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-1(6H)-yl)benzoate

A mixture of methyl3-(3-chloro-5-methyl-6-oxopyridazin-1(6H)-yl)-4-methylbenzoate(Intermediate X19; 425 mg, 1.45 mmol), bis(pinacolato)diboron (553 mg,2.18 mmol), Pd(OAc)₂ (32.6 mg, 0.145 mmol), X-Phos (104 mg, 0.218 mmol),and KOAc (427 mg, 4.36 mmol) in dioxane (14.5 mL) was sparged withN_(2(g)), then sealed and stirred for 6 h at 100° C. After cooling toambient temperature, the reaction mixture was diluted with 4:1 DCM:iPrOH(100 mL) then extracted with water (2×30 mL). The organic extracts weredried over anhydrous MgSO_(4(s)), filtered and concentrated under vacuumto afford the crude title compound. MS (apci) m/z=384.1 (M+), 259.0[(M-B(OR)₂)+H]. This material was of sufficient purity to be useddirectly without further purification.

Intermediate R22

4-cyclobutyl-2-(3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one

A solution of6-chloro-4-cyclobutyl-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Intermediate X22; 149.6 mg, 0.4664 mmol) in dioxane (5.0 mL) wastreated with bis(pinacolato)diboron (130.3 mg, 0.5130 mmol), Pd(OAc)₂(10.47 mg, 0.04664 mmol), X-Phos (33.35 mg, 0.06996 mmol), and KOAc(137.3 mg, 1.399 mmol). The mixture was sparged with Ar_((g)), thensealed and stirred for 1 h at 100° C. After cooling to ambienttemperature, the reaction mixture was diluted with 4:1 DCM:iPrOH (50 mL)and then extracted with water (2×25 mL). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum toafford the title compound (192.2 mg, 100% yield). MS (apci) m/z=261.0(B(OH)₂ M+H), 217.1 (M-B(OR)₂+H). This material was of sufficient purityto be used directly without further purification.

The following intermediates shown in Table R22 were prepared accordingthe method used for the synthesis of Intermediate R22 using theappropriate starting materials (Intermediates X23-X27). Reactionprogression in each was followed by LCMS and reaction time was adjustedas necessary.

TABLE R22 Intermediate Structure Name R23

2-(3,5-dimethoxyphenyl)-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one R24

4-cyclopropyl-2-(3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one R25

2-(3,5-dimethoxyphenyl)-4-isobutyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one R26

2-(3,5-dimethoxyphenyl)-4-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one R27

2-(3,5-dimethoxyphenyl)-4-propyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one

Intermediate R28

2-(2-chloro-6-fluoro-3-methoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one

A solution of6-chloro-2-(2-chloro-6-fluoro-3-methoxyphenyl)pyridazin-3(2H)-one(ArkPharm, 180 mg, 0.622 mmol), bis(pinacolato)diboron (316 mg, 1.24mmol), palladium(II) acetate (14.0 mg, 0.062 mmol), X-PHOS (45 mg, 0.093mmol), and potassium acetate (183 mg, 1.87 mmol). was degassed withnitrogen, sealed, and heated to 100° C. overnight (16 hrs). The mixturewas cooled to ambient temperature then diluted with 4:1 DCM:IPA andwashed with water. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was carried forward to next step withoutfurther purification. LCMS (APCI+) m/z=255.0; retention time 1.60 min.

Intermediate R29

2-(2,6-difluoro-3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one

A solution of6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one(ArkPharm 163 mg, 0.539 mmol), bis(pinacolato)diboron (274 mg, 1.08mmol), palladium(II) acetate (12.1 mg, 0.0539 mmol), X-PHOS (38.5 mg,0.081 mmol), and potassium acetate (159 mg, 1.62 mmol) was sparged withnitrogen, sealed, and heated to 100° C. for 16 h. The reaction mixturewas cooled to ambient temperature, then diluted with 4:1 DCM:IPA, washedwith water, dried over Na₂SO₄, filtered through fluted filter paper andconcentrated. The residue was used without further purification inexcess in a subsequent reaction. LCMS (APCI+) m/z 269.1 (fragment:M-pinacolboronate); Retention time=1.70 min.

Intermediate R30

2-(3-methylquinolin-7-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one

A mixture of 6-chloro-2-(3-methylquinolin-7-yl)pyridazin-3 (2H)-one(Intermediate X29; 25 mg, 0.09 mmol), Bis(Pinacolato)diboron (70.1 mg,0.28 mmol), Pd(OAc)₂ (2.1 mg, 0.01 mmol), and XPHOS (6.6 mg, 0.01 mmol)in dioxane (0.6 mL) was sparged with Ar_((g)) for 5 min at ambienttemperature, then stirred for 3 h at 90° C. After cooling to ambienttemperature, the reaction mixture was partitioned between EtOAc andwater. The organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum to affordthe title compound (21.8 mg, 99% yield). MS (apci) m/z=238.1(M-B(OR)₂+H). This material was of sufficient purity to be used directlywithout further purification.

Intermediate R31

Methyl4-methyl-3-(5-methyl-6-oxo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-1(6H)-yl)benzoate

A glass pressure tube was charged with Intermediate X30 [methyl3-(3-chloro-5-methyl-6-oxopyridazin-1(6H)-yl)-4-methylbenzoate] (425 mg,1.45 mmol), bis(pinacolato)diboron (553 mg, 2.2 mmol), palladium (II)acetate (33 mg, 0.145 mmol), XPHOS (104 mg, 0.22 mmol), potassiumacetate (427.5 mg, 4.4 mmol) and 1,4-dioxane (14519 μL, 1.45 mmol). Themixture was sparged with N2. The tube was sealed with a Teflon screw capand heated at 100° C. with stirring for 6 hrs. The mixture was thencooled to 0° C., diluted with 4:1 DCM:IPA (100 mL) and washed withwater. The organic layer was separated, dried over MgSO₄ andconcentrated under reduced pressure. The crude product was usedimmediately in a subsequent reaction.

Intermediate M1

3-(3-(2-amino-5-bromopyridin-3-yl)-6-oxopyridazin-1(6H)-yl)-N-methylbenzamideStep 1: Preparation of Methyl3-(3-(2-aminopyridin-3-yl)-6-oxopyridazin-1(6H)-yl)benzoate

A solution of methyl 3-(3-chloro-6-oxopyridazin-1(6H)-yl)benzoate(Intermediate X16; 531.9 mg, 2.010 mmol) in 4:1 dioxane:water (15 mL)was treated with t-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate(643.5 mg, 2.010 mmol), Pd(PPh₃)₄ (232.2 mg, 0.2010 mmol), K₂CO_(3(s))(833.3 mg, 6.029 mmol). The mixture was sparged with Ar_((g)), thensealed and stirred for 16 h at 100° C. After cooling to ambienttemperature, the reaction mixture was diluted with EtOAc (200 mL), andthe resulting solution was extracted with water (2×50 mL) then brine (25mL). The organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated under vacuum. The resulting crude residue waspurified by C18 reverse phase chromatography (2-75% water/ACN with 0.1%TFA as the gradient eluent) to afford the title compound as a TFA salt.The TFA salt was dissolved in 4:1 DCM:iPrOH (50 mL) and extracted withsaturated NaHCO_(3(aq)) (1×25 mL). The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum cleanlyaffording the title compound (160.5 mg, 25% yield). MS (apci) m/z=323.1(M+H).

Step 2: Preparation of Methyl3-(3-(2-amino-5-bromopyridin-3-yl)-6-oxopyridazin-1(6H)-yl)benzoate

A solution of methyl3-(3-(2-aminopyridin-3-yl)-6-oxopyridazin-1(6H)-yl)benzoate (from step1; 160.5 mg, 0.4980 mmol) in ACN (5.0 mL) was treated with NBS (97.49mg, 0.5478 mmol) then stirred for 16 h at ambient temperature thenconcentrated under vacuum. The resulting residue was triturated withEtOAc (10 mL) filtered to afford the title compound (169.0 mg, 85%yield). MS (apci) m/z=403.0 [(M+H)+2], 401.0 (M+H), with Br pattern.

Step 3: Preparation of3-(3-(2-amino-5-bromopyridin-3-yl)-6-oxopyridazin-1(6H)-yl)benzoic Acid

A solution of methyl3-(3-(2-amino-5-bromopyridin-3-yl)-6-oxopyridazin-1(6H)-yl)benzoate(from step 2; 142.8 mg, 0.3559 mmol) in 1:1 THF:MeOH (3.6 mL) wastreated with 2 M KOH_((aq)) (889.8 μL, 1.780 mmol) then stirred for 1 hat 70° C. After cooling to ambient temperature, the reaction mixture wasdiluted with water (10 mL). The resulting suspension was filtered, andthe filter cake was washed with water (2×10 mL). The solids were driedunder high vacuum for 16 h at 55° C. to afford the title compound (93.8mg, 68% yield). MS (apci) m/z=389.0 [(M+H)+2], 387.0 (M+H), with Brpattern.

Step 4: Preparation of3-(3-(2-amino-5-bromopyridin-3-yl)-6-oxopyridazin-1(6H)-yl)-N-methylbenzamide

A solution of methyl3-(3-(2-amino-5-bromopyridin-3-yl)-6-oxopyridazin-1(6H)-yl)benzoic acid(from step 3; 93.8 mg, 0.242 mmol) in DMF (2.5 mL) was treated withmethylamine hydrochloride (49.1 mg, 0.727 mmol), HATU (110 mg, 0.291mmol), and DIPEA (211 μL, 1.21 mmol). The resulting mixture was stirredfor 2 h at ambient temperature before directly chromatographing thereaction mixture using C18 reverse phase chromatography (5-95% water/ACNw/0.1% TFA as the gradient eluent) to afford the title compound as theTFA salt. The TFA salt was dissolved in 4:1 DCM:iPrOH (25 mL) andextracted with saturated NaHCO_(3(aq)) (1×10 mL). The organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered and concentrated undervacuum cleanly affording the title compound (47.6 mg, 49% yield). MS(apci) m/z=402.0 [(M+H)+2], 400.0 (M+H), with Br pattern.

Intermediate M2

6-(2-amino-5-bromopyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one Step 1: Preparation of6-(2-aminopyridin-3-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of t-Butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate(923.4 mg, 2.884 mmol) in 4:1 dioxane:water (15 mL) was treated with6-chloro-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one (Intermediate X8;807.5 mg, 3.028 mmol), Pd(PPh₃)₄(333.2 mg, 0.2884 mmol), K₂CO_(3(s))(1195 mg, 8.652 mmol). The mixture was sparged with Ar_((g)), thensealed and stirred for 16 h at 100° C. After cooling to ambienttemperature, the reaction mixture was diluted with 4:1 DCM:iPrOH (100mL), and the resulting solution was extracted with water (2×50 mL). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum. The resulting crude residue was purified bysilica chromatography (1-25% DCM/MeOH as the gradient eluent) to affordthe title compound (505.5 mg, 54% yield). MS (apci) m/z=325.1 (M+H).

Step 2: Preparation of6-(2-aminopyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A cold (0° C.) solution of6-(2-aminopyridin-3-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one (fromstep 1; 12.7 mg, 0.0392 mmol) in ACN (0.8 mL) was treated with SO₂Cl₂(6.33 μL, 0.0783 mmol) then stirred for 30 min at ambient temperature.The resulting mixture was quenched with the addition of saturatedNaHCO_(3(aq)) (10 mL). The resulting biphasic mixture was extracted with4:1 DCM:iPrOH (2×25 mL). The combined organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum to affordthe title compound (13.1 mg, 85% yield). MS (apci) m/z=396.9 [(M+H)+4],394.9 [(M+H)+2], 392.9 (M+H), with di Cl pattern.

Step 3: Preparation of6-(2-amino-5-bromopyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of6-(2-aminopyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one(from step 2; 12.0 mg, 0.0305 mmol) in ACN (0.6 mL) was treated with NBS(5.97 mg, 0.0336 mmol) then stirred for 16 h at ambient temperature. Theresulting mixture was diluted with 4:1 DCM:iPrOH (25 mL) and extractedwith water (2×10 mL). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated under vacuum to afford the titlecompound (14.4 mg, 100% yield). MS (apci) m/z=474.9 [(M+H)+4], 472.9[(M+H)+2], 470.9 (M+H) with di Cl pattern.

Intermediate M3

6-(3-amino-6-bromopyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

3,5-Dibromopyrazin-2-amine (0.417 g, 1.65 mmol) and sodium carbonate(2.62 ml, 5.24 mmol) were added to a solution of2-(2,6-dichloro-3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one (Intermediate R17; 0.640 g, 1.50 mmol) in 1,4-dioxane (15.0 ml,1.50 mmol). The reaction mixture was stirred at 55° C. for 20 hrs. Thereaction was quenched with water (50 mL) and extracted with DCM. Thecombined organic extracts were washed with water and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was triturated with DCM(50 mL) and filtered to obtain title compound (0.207 g, 0.438 mmol,29.2% yield). MS (apci) m/z=477.9 [(M+H)+4], 475.9 [(M+H)+2], 473.9(M+H), 471.9 (M−H) with di Cl+Br pattern.

Intermediate M4

6-(3-amino-6-bromopyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one

A mixture of 3,5-dibromopyrazin-2-amine (0.585 g, 2.31 mmol),2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R16; 0.927 g, 2.10 mmol), Pd(PPh₃)₄(0.182 g, 0.158 mmol)and Na₂CO₃ (2.21 mL, 4.41 mmol) in dioxane (10.5 ml, 2.10 mmol) wasstirred at 55° C. for 8 hours. The reaction was quenched with water andextracted with DCM. The combined organic extracts were washed with waterand brine, dried over Na₂SO₄ and concentrated in vacuo. The cruderesidue was purified by flash chromatography (1-9% MeOH in DCM) to givethe title compound (0.187 g, 0.384 mmol, 18.3% yield). MS (apci)m/z=491.9 [(M+H)+4], 489.9 [(M+H)+2], 487.9 (M+H), 485.9 (M−H) with diCl+Br pattern

Preparation of Synthetic Examples Example 1

6-(3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of2-(3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R8; 275.0 mg, 0.7677 mmol) in 4:1 dioxane:water (7.7 mL)was treated with 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine(Intermediate L2; 204.8 mg, 0.8061 mmol), PdCl₂(dppf).CH₂Cl₂ (63.16 mg,0.07677 mmol), K₂CO_(3(s)) (318.3 mg, 2.303 mmol). The resulting mixturewas sparged with Ar_((g)), then sealed and stirred for 16 h at 100° C.After cooling to ambient temperature, the reaction mixture was dilutedwith 4:1 DCM:iPrOH (150 mL), and extracted with water (2×50 mL). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum. The resulting crude residue was purified bysilica chromatography (5-80% DCM/Acetone as the gradient eluent) toafford the title compound (189.6 mg, 61% yield). MS (apci) m/z=406.1(M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 8.67-8.65 (d, 1H), 8.48 (s, 1H), 8.30(s, 1H), 8.02 (s, 1H), 7.31 (s, 2H), 7.22-7.20 (d, 1H), 6.86-6.85 (d,2H), 6.63-6.62 (m, 1H), 3.89 (s, 3H), 3.79 (s, 6H).

The following compounds shown in Table 1 were prepared according themethod used in Example 1 using the appropriate3-bromo-5-(pyrazoyl)pyrazin-2-amines (Intermediates L2, L14, L15, L16,L19) and2-(Aryl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R1, R8, R9; 1.00-1.2 equivalents). Reaction progression ineach was followed by LCMS and reaction time was adjusted as necessary.All compounds were purified using a method similar to that followed inExample 1 utilizing the appropriate gradient eluent.

TABLE 1 MS (apci) Ex # Structure Name m/z 2*

6-(3-amino-6-(1- methyl-1H-pyrazol- 4-yl)pyrazin-2-yl)-2- (3-methoxyphenyl)pyridazin- 3(2H)-one 376.0 (M + H) 3

6-(3-amino-6-(1- methyl-1H-pyrazol- 4-yl)pyrazin-2-yl)-2- (3,4-dimethoxyphenyl)pyridazin- 3(2H)-one 406.1 (M + H) 4

1-((4-(5-amino-6-(1- (3,5- dimethoxyphenyl)-6- oxo-1,6-dihydropyridazin-3- yl)pyrazin-2-yl)-1H- pyrazol-1-yl)methyl)cyclopropane- 1-carbonitrile 471.1 (M + H) 5

6-(3-amino-6-(1- (4,4,4-trifluoro-2- hydroxybutyl)-1H-pyrazol-4-yl)pyrazin- 2-yl)-2-(3,5- dimethoxyphenyl)pyridazin- 3(2H)-one518.0 (M + H) 6

2-(4-(5-amino-6-(1- (3,5- dimethoxyphenyl)-6- oxo-1,6-dihydropyridazin-3- yl)pyrazin-2-yl)-1H- pyrazol-1-yl)-2-methylpropanenitrile 459.1 (M + H) 7

6-(3-amino-6-(1-(1- hydroxy-2- methylpropan-2-yl)- 1H-pyrazol-4-yl)pyrazin-2-yl)-2- (3,5- dimethoxyphenyl)pyridazin- 3(2H)-one 464.1(M + H) *EtOAc was used as the work up solvent in place of 4:1 DCM iPrOH

Example 8

6-(3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3-methoxy-5-(trifluoromethoxy)phenyl)pyridazin-3(2H)-one2,2,2-trifluoroacetate Salt

A suspension of 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine(Intermediate L2; 0.100 g, 0.394 mmol),2-(3-methoxy-5-(trifluoromethoxy)phenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R2; 0.243 g, 0.590 mmol), Pd(PPh₃)₄(0.0341 g, 0.0295 mmol)and 2M Na₂CO_(3(aq)) (0.413 mL, 0.826 mmol) in dioxane (1.0 mL) wassparged with Ar_((g)), then sealed and stirred for 8 h at 90° C. Aftercooling to ambient temperature, the reaction mixture was filtered toremove solids. The filtrate was concentrated under vacuum, and theresulting crude residue was purified by C18 reverse phase chromatography(5-95% ACN:water with 0.1% TFA) to afford the title compound (0.1014 g,46% yield). MS (apci) m/z=460.1 (M+H).

The following compounds shown in Table 2, were prepared according themethod used in Example 8 using the appropriate3-bromo-5-(pyrazoyl)pyrazin-2-amines (Intermediates L2, L3, L5, L17) and2-(Aryl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R3, R4, R6, R7, R8, R12). Reaction progression in each wasfollowed by LCMS and reaction time was adjusted as necessary. Allcompounds were purified using a method similar to that used in Example 8utilizing the appropriate gradient eluent and in each case the mono-TFAsalt was isolated.

TABLE 2 MS (apci) Ex # Structure Name m/z  9

6-(3-amino-6-(1- methyl-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(3- ethoxy-5-(trifluoromethoxy)phenyl)pyridazin- 3(2H)-one 2,2,2-trifluoroacetatesalt 474.1 (M + H) 10

6-(3-amino-6-(1- methyl-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(3- methoxy-5-(trifluoromethyl)phenyl)pyridazin- 3(2H)-one 2,2,2-trifluoroacetate salt444.1 (M + H) 11

6-(3-amino-6-(1- methyl-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(2- chloro-3-methoxyphenyl)pyridazin- 3(2H)-one 2,2,2- trifluoroacetate salt 410.1(M + H) 12

6-(3-amino-6-(1- methyl-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(o-tolyl)pyridazin-3(2H)- one 2,2,2- trifluoroacetate salt 360.1 (M + H) 13

3-(3-(3-amino-6-(1- methyl-1H-pyrazol-4- yl)pyrazin-2-yl)-6-oxopyridazin-1(6H)- yl)-5- methoxybenzonitrile 2,2,2-trifluoroacetatesalt 401.1 (M + H) 14

6-(3-amino-6-(1- methyl-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(2- chloro-3,5-dimethoxyphenyl)pyridazin- 3(2H)-one (2,2,2- trifluoroacetate) salt440.1 (M + H) 15

6-(3-amino-6-(1- isopropyl-1H-pyrazol- 4-yl)pyrazin-2-yl)-2- (3,5-dimethoxyphenyl)pyridazin- 3(2H)-one 2,2,2- trifluoroacetate 434.1 (M +H) 16

6-(3-amino-6-(1- (pentan-3-yl)-1H- pyrazol-4-yl)pyrazin-2- yl)-2-(3,5-dimethoxyphenyl)pyridazin- 3(2H)-one 2,2,2- trifluoroacetate salt 462.2(M + H) 17

6-(3-amino-6-(1- (cyclopropylmethyl)- 1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin- 3(2H)-one 2,2,2-trifluoroacetate salt 446.2 (M + H) 18

6-(3-amino-6-(1-(2- hydroxy-2- methylpropyl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin- 3(2H)-one 2,2,2- trifluoroacetatesalt 464.2 (M + H)

Example 19

6-(3-amino-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A suspension of3-bromo-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazin-2-amine(Intermediate L8; 0.044 g, 0.125 mmol),2-(3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R8; 0.0892 g, 0.249 mmol), Pd(PPh₃)₄ (0.0108 g, 0.00934mmol) and 2M Na₂CO_(3(aq)) (0.131 mL, 0.262 mmol) in dioxane (1 mL) wassparged with Ar_((g)), then sealed and stirred for 8 h at 90° C. Aftercooling to ambient temperature, the reaction mixture was filtered toremove solids. The filtrate was concentrated under vacuum, and theresulting crude residue was purified by silica chromatography (5-95%DCM:(DCM:MeOH:NHOH₄ (90:10:1)) to afford the title compound (0.0538 g,86% yield). MS (apci) m/z=505.2 (M+H).

The following compounds shown in Table 3 were prepared according themethod used in Example 19 using the appropriate3-bromo-5-(pyrazoyl)pyrazin-2-amines (Intermediates L2, L4, L7) and2-(Aryl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R5, R8). Reaction progression in each was followed by LCMSand reaction time was adjusted as necessary. All compounds were purifiedusing a method similar to that followed in Example 19 utilizing theappropriate gradient eluent.

TABLE 3 MS (apci) Ex # Structure Name m/z 20

6-(3-amino-6-(1- methyl-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(3-isopropoxy-5- methoxyphenyl)pyridazin- 3(2H)-one 434.2 (M + H) 21

6-(3-amino-6-(1- isobutyl-1H-pyrazol- 4-yl)pyrazin-2-yl)-2- (3,5-dimethoxyphenyl)pyridazin- 3(2H)-one 448.2 (M + H) 22

6-(3-amino-6-(1- cyclobutyl-1H- pyrazol-4-yl)pyrazin- 2-yl)-2-(3,5-dimethoxyphenyl)pyridazin- 3(2H)-one 446.2 (M + H)

Example 23

6-(3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A cold (0° C.) solution of6-(3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 1; 13.6 mg, 0.0335 mmol) in ACN (0.7 mL) was treated withSO₂Cl₂ (5.42 μL, 0.0671 mmol) then stirred for 30 min at ambienttemperature. The resulting mixture was quenched with the addition ofsaturated NaHCO_(3(aq)) (10 mL). The resulting biphasic mixture wasextracted with 4:1 DCM:iPrOH (2×25 mL). The combined organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered and concentrated undervacuum. The resulting crude residue was purified by silicachromatography (5-50% DCM/Acetone as the gradient eluent) to afford thetitle compound (189.6 mg, 61% yield). MS (apci) m/z=476.0 [(M+H)+2],474.1 (M+H), with di Cl pattern. ¹H NMR (400 MHz, DMSO-d₆) δ 8.73-8.70(d, 1H), 8.47 (s, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.30-7.27 (d, 1H),7.09 (s, 1H), 7.03 (s, 2H), 3.94 (s, 6H), 3.85 (s, 3H).

Example 24

6-(3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2-bromo-3,5-dimethoxyphenyl)pyridazin-3(2H)-one2,2,2-trifluoroacetate Salt

A cold (0° C.) solution of6-(3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 1; 100 mg, 0.247 mmol) in DCM (1.23 mL) was treated with NBS(43.9 mg, 0.247 mmol) then stirred for 3 h at ambient temperature. Theresulting mixture was diluted with Ethyl Acetate, washed with Brine(2x), then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedunder vacuum. The resulting crude residue was purified by silica gelchromatography (30-100% EtOAc/Hexanes as the gradient eluent) to affordthe title compound in about 75% purity (17.4 mg, 15% yield). Additionalpurification by C18 reverse phase chromatography (5-95% Acetonitrile inWater with 0.1% TFA as gradient eluent) provided clean title compound.MS (apci) m/z=484.0 (M+H), with di Br pattern. 1H NMR (400 MHz, CDCl₃) δ8.67-8.64 (d, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.20-7.17(d, 1H), 6.65-6.60 (m, 2H), 6.27 (broad s, 2H), 3.96 (s, 3H), 3.92 (s,3H), 3.82 (s, 3H).

Example 25

6-(3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dibromo-3,5-dimethoxyphenyl)pyridazin-3(2H)-one2,2,2-trifluoroacetate Salt

A cold (0° C.) solution of6-(3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 1; 20 mg, 0.0493 mmol) in DCM (0.247 mL mL) was treated withNBS (15 mg, 0.0843 mmol) then stirred overnight at ambient temperature.The resulting mixture was diluted with Ethyl Acetate, washed with Brine(2x), then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedunder vacuum. The resulting crude residue was purified by C18 reversephase chromatography (5-95% Acetonitrile in Water with 0.1% TFA as thegradient) to afford the title compound (7 mg, 25% yield). MS (apci)m/z=564.0 (M+H), with di Br pattern. ¹H NMR (400 MHz, CDCl₃) δ 8.84-8.81(d, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.27-7.24 (d, 1H),6.95 (s, 1H), 4.00 (s, 6H), 3.94 (s, 3H).

Example 26

(R)-6-(3-amino-6-(1-((5,5-dimethylmorpholin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one Step 1: Preparation of tert-butyl(R)-2-((4-(5-amino-6-(1-(3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5,5-dimethylmorpholine-4-carboxylate

A suspension of tert-butyl(R)-2-((4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5,5-dimethylmorpholine-4-carboxylate(Intermediate L12; 100 mg, 0.214 mmol),2-(3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R8; 192 mg, 0.535 mmol), Pd(PPh₃)₄(24.7 mg, 0.0214 mmol),and 2M Na₂CO_(3(aq)) (321 μL, 0.642 mmol) in dioxane (2.14 mL) wassparged with Ar_((g)), then sealed and stirred 2 h at 90° C. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc and filtered to remove solids. The filtrate was concentrated undervacuum, and the resulting crude residue was purified by silicachromatography (60-100% EtOAc in Hexanes) to afford the title compound(35 mg, 26% yield). MS (apci) m/z=619.2 (M+H).

Step 2: Preparation of(R)-6-(3-amino-6-(1-((5,5-dimethylmorpholin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

The tert-butyl(R)-2-((4-(5-amino-6-(1-(3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5,5-dimethylmorpholine-4-carboxylate(35 mg, 0.057 mmol) was dissolved in 1:1 TFA:DCM (8.0 mL) then stirred 1h at ambient temperature. The reaction mixture was concentrated undervacuum then purified by C18 reverse phase chromatography (5-95% ACN inH₂O with 0.1% TFA as the gradient as the gradient eluent). Thechromatographic fractions containing the title compound were combinedthen neutralized with saturated NaHCO_(3(aq)) and extracted with DCM.The organic extracts were then dried over anhydrous Na₂SO_(4(s)),filtered and concentrated under vacuum to afford the title compound(24.5 mg, 84% yield). MS (apci) m/z=519.2 (M+H).

Example 27

(S)-6-(3-amino-6-(1-((5,5-dimethylmorpholin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one Step 1: Preparation of Tert-Butyl(S)-2-((4-(5-amino-6-(1-(3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5,5-dimethylmorpholine-4-carboxylate

The title compound was prepared and isolated according to the methoddescribed in step 1 of Example 26, using tert-butyl(S)-2-((4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5,5-dimethylmorpholine-4-carboxylate(Intermediate L11) in place of tert-butyl(R)-2-((4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5,5-dimethylmorpholine-4-carboxylate(Intermediate L12). The title compound was carried on to step 2, withoutsilica chromatography. MS (apci) m/z=446.2 (M+H).

Step 2: Preparation of(S)-6-(3-amino-6-(1-((5,5-dimethylmorpholin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

The title compound was prepared and isolated according to the methoddescribed in step 2 of Example 26, using the crude residue from step 1and neutralizing with 1 M NaOH_((aq)) instead of NaHCO_(3(aq)) resultingin a 46% yield (39 mg). MS (apci) m/z=519.2 (M+H).

Example 28

6-(3-amino-6-(1-(((2S,5R)-5-methylmorpholin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one Step 1: Preparation of tert-butyl(2S,5R)-2-((4-(5-amino-6-(1-(3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5-methylmorpholine-4-carboxylate

The title compound was prepared and isolated according to the methoddescribed in step 1 of Example 26, with the exception that the reactionrequired overnight stirring at 90° C. and utilized tert-butyl(2S,5R)-2-((4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5-methylmorpholine-4-carboxylate(Intermediate L10) in place of tert-butyl(R)-2-((4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5,5-dimethylmorpholine-4-carboxylate(Intermediate L12). The title compound was carried on to step 2, withoutsilica chromatography (23 mg, 34% yield). MS (apci) m/z=605.2 (M+H).

Step 2: Preparation of6-(3-amino-6-(1-(((2S,5R)-5-methylmorpholin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

Using the crude residue from step 1, the title compound was prepared,isolated, purified and neutralized according to the method described instep 2 of Example 26, with the exception that the reaction was allowedto stir 2 d at ambient temperature prior to isolation/purification (7.0mg, 84% yield). MS (apci) m/z=505.2 (M+H).

Example 29

(R)-6-(6-(1-((7-oxa-4-azaspiro[2.5]octan-6-yl)methyl)-1H-pyrazol-4-yl)-3-aminopyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one Step 1: Preparation of Tert-Butyl(R)-6-((4-(5-amino-6-(1-(3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate

The title compound was prepared and isolated according to the methoddescribed in step 1 of Example 26, using of tert-butyl(R)-6-((4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate(Intermediate L13) in place of tert-butyl(R)-2-((4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5,5-dimethylmorpholine-4-carboxylate(Intermediate L12). The title compound was purified by silicachromatography (30-75% EtOAc in Hexanes) which provide the titlecompound in 38% yield (15 mg). MS (apci) m/z=617.2 (M+H).

Step 2: Preparation of(R)-6-(6-(1-((7-oxa-4-azaspiro[2.5]octan-6-yl)methyl)-1H-pyrazol-4-yl)-3-aminopyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

Using the purified material from step 1, the title compound wasprepared, isolated, purified and neutralized according to the methoddescribed in step 2 of Example 27 (12.1 mg, 96% yield). MS (apci)m/z=517.2 (M+H).

Example 30

6-(3-amino-6-(1-(((2R,5R)-5-methylmorpholin-2-yl)methy)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one Step 1: Preparation of tert-butyl(2R,5R)-2-((4-(5-amino-6-(1-(3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5-methylmorpholine-4-carboxylate

The title compound was prepared and isolated according to the methoddescribed in step 1 of Example 26, using of tert-butyl(2R,5R)-2-((4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5-methylmorpholine-4-carboxylate(Intermediate L9) in place of tert-butyl(R)-2-((4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)methyl)-5,5-dimethylmorpholine-4-carboxylate(Intermediate L12). The title compound was purified by silicachromatography (30-75% EtOAc in Hexanes) which provided the titlecompound in 31% yield (23 mg). MS (apci) m/z=605.2 (M+H).

Step 2: Preparation of6-(3-amino-6-(1-(((2R,5R)-5-methylmorpholin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

Using the purified material from step 1, the title compound wasprepared, isolated, purified according to the method described in step 2of Example 26 which provided the title compound in 91% yield (17.4 mg).MS (apci) m/z=505.2 (M+H).

Example 31

6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one Step 1: Preparation of Tert-Butyl4-(4-(5-amino-6-(1-(3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A suspension of tert-butyl4-(4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate L19; 398.9 mg, 0.9423 mmol),2-(3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R8; 371.3 mg, 1.037 mmol), PdCl₂(dppf).CH₂Cl₂ (77.52 mg,0.09423 mmol) and K₂CO_(3(s)) (390.7 mg, 2.827 mmol) in 4:1dioxane:water (10 mL) was sparged with Ar_((g)), then sealed and stirred16 h at 100° C. After cooling to ambient temperature, the reactionmixture was diluted with 4:1 DCM:iPrOH (200 mL) and washed with water(2×50 mL). The organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated under vacuum. The crude residue was purifiedby silica chromatography (5-95% DCM-Acetone as the gradient eluent) toafford the title compound which was immediately carried on to step 2. MS(apci) m/z=575.3 (M+H).

Step 2: Preparation of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

The tert-butyl4-(4-(5-amino-6-(1-(3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylatewas dissolved in 1:1 TFA:DCM (5.0 mL) then stirred 30 min at ambienttemperature. The reaction mixture was concentrated under vacuum thenpurified by C18 reverse phase chromatography (5-95% ACN in H₂O with 0.1%TFA as the gradient eluent) to afford the title compound as a TFA salt.The TFA salt was dissolved in 4:1 DCM:iPrOH (50 mL) and extracted withsaturated NaHCO_(3(aq)) (1×25 mL). The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum tocleanly afford the title compound (213.2 mg, 48% yield). MS (apci)m/z=475.2 (M+H).

Example 32

6-(3-amino-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 31; 187.2 mg, 0.3945 mmol) in 1:1 DCM:MeOH (4 mL) was treatedwith formaldehyde (592.9 μL, 7.890 mmol) and stirred 15 min at ambienttemperature. The resulting reaction mixture was treated with sodiumtriacetoxyborohydride (334.4 mg, 1.578 mmol) and stirred 16 h at ambienttemperature. The reaction mixture was concentrated under vacuum thenpurified by C18 reverse phase chromatography (5-95% water-ACN w/0.1% TFAas the gradient eluent) to afford the title compound as a TFA salt. TheTFA salt was dissolved in 4:1 DCM:iPrOH (50 mL) and extracted withsaturated NaHCO_(3(aq)) (1×25 mL). The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum to affordthe title compound along with imine contaminants. The residue then wasdissolved in 1:1:1 TFA:ACN:water (6 mL) and stirred for 15 min atambient temperature then concentrated under vacuum. The resultantresidue was dissolved in 4:1 DCM:iPrOH (50 mL) and extracted withsaturated NaHCO_(3(aq)) (1×25 mL). The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum. Theresidue was purified further by silica chromatography (1-30% DCM-MeOHw/2% NH₄OH as the gradient eluent) to cleanly afford the title compound(28.5 mg, 15% yield). MS (apci) m/z=489.1 (M+H). ¹H NMR (400 MHz,DMSO-d₆) δ 8.71-8.69 (d, 1H), 8.49 (s, 1H), 8.42 (s, 1H), 8.04 (s, 1H),7.31 (s, 2H), 7.21-7.19 (d, 1H), 6.86-6.85 (d, 2H), 6.63-6.62 (t, 1H),4.19-4.13 (m, 1H), 3.79 (s, 6H), 2.93-2.88 (m, 2H), 2.25 (s, 3H),2.15-1.97 (m, 6H).

Example 33

6-(3-amino-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 31; 10.6 mg, 0.0223 mmol) in DMF (0.5 mL) was treated with1-bromo-2-methoxyethane (2.5 μL, 0.027 mmol) and K₂CO_(3(s)) (6.1 mg,0.0447 mmol). The resulting mixture was stirred 16 h at ambienttemperature, then additional 1-bromo-2-methoxyethane (2.5 μL, 0.027mmol) and K₂CO_(3(s)) (6.1 mg, 0.0447 mmol) were added. The reaction wasstirred for an additional period of 24 h at ambient temperature andsubsequently diluted with EtOAc (25 mL). The EtOAc solution was washedwith water (2×10 mL) and brine (1×10 mL). The organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated undervacuum. The crude residue was purified by silica chromatography (1-30%DCM-MeOH w/2% NH₄OH as the gradient eluent) to afford the title compound(6.1 mg, 51% yield). MS (apci) m/z=533.2 (M+H). ¹H NMR (400 MHz,DMSO-d₆) δ 8.72-8.70 (d, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 8.04 (s, 1H),7.31 (s, 2H), 7.21-7.18 (d, 1H), 6.86-6.85 (d, 2H), 6.63-6.62 (t, 1H),4.19-4.12 (m, 1H), 3.79 (s, 6H), 3.47-3.44 (t, 2H), 3.25 (s, 3H),3.01-2.97 (m, 2H), 2.54-2.51 (m, 2H), 2.19-2.13 (m, 2H), 2.06-1.94 (m,4H).

Example 34

6-(3-amino-6-(1-(1-(2-(trifluoromethoxy)ethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one2,2,2-trifluoroacetate Salt

A solution of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 31; 100 mg, 0.211 mmol) in DMSO (843 μL) was treated with1-bromo-2-(trifluoromethoxy)ethane (36.4 μL, 0.316 mmol) andCs₂CO_(3(s)) (172 mg, 0.527 mmol). The resulting mixture was stirredovernight at ambient temperature then diluted with EtOAc and washed withwater (2x) and brine. The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated under vacuum. The crude residuewas purified by silica chromatography (50-100% EtOAc in Hexanes as thegradient eluent). The material was further purified by C18 reverse phasechromatography (5-95% Acetonitrile in Water with 0.1% TFA as thegradient eluent) to afford the title compound (15 mg, 12% yield). MS(apci) m/z=587.2 (M+H).

Example 35

6-(3-amino-6-(1-(1-(2,2-difluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one2,2,2-trifluoroacetate Salt

A solution of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 31; 100 mg, 0.211 mmol) in DMF (1.05 mL) was treated with DIPEA(110 μL, 0.632 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate(67.7 mg, 0.316 mmol). The resulting mixture was stirred 4 h at ambienttemperature then diluted with EtOAc and washed with water and brine. Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum. The crude residue was purified by silicachromatography (stepwise gradient eluent of 70-100% EtOAc in Hexanesthen 0-5% MeOH in EtOAc). The material was further purified by C18reverse phase chromatography (5-95% Acetonitrile in Water with 0.1% TFAas the gradient eluent) to afford the title compound (11 mg, 10% yield).MS (apci) m/z=539.2 (M+H).

Example 36

6-(3-amino-6-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 31; 100 mg, 0.211 mmol) in DMF (1.05 mL) was treated with DIPEA(110 μL, 0.632 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate(73.4 mg, 0.316 mmol). The resulting mixture was stirred over theweekend at ambient temperature then diluted with a mixture ofEtOAc/water/brine. The organic extracts were washed with water and brinethen dried over anhydrous MgSO_(4(s)), filtered and concentrated undervacuum. The crude residue was purified by silica chromatography (50-80%EtOAc in Hexanes as the gradient eluent) to afford the title compound(30.2 mg, 26% yield). MS (apci) m/z=557.2 (M+H).

Example 37

6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(5-methoxy-2-methylphenyl)pyridazin-3(2H)-one Step 1: Preparation of tert-butyl4-(4-(5-amino-6-(1-(5-methoxy-2-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A suspension of tert-butyl4-(4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate L19; 198.5 mg, 0.4689 mmol),2-(5-methoxy-2-methylphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R¹⁰; 320.9 mg, 0.9379 mmol), PdCl₂(dppf).CH₂Cl₂ (38.58 mg,0.04689 mmol) and K₂CO_(3(s)) (194.4 mg, 1.407 mmol) in 4:1dioxane:water (5.0 mL) was sparged with Ar_((g)), then sealed andstirred 16 h at 100° C. After cooling to ambient temperature, thereaction mixture was diluted with 4:1 DCM:iPrOH (50 mL) and washed withwater (2×25 mL). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated under vacuum. The crude residuewas purified by silica chromatography (5-60% DCM-Acetone as the gradienteluent) to afford the title compound which was immediately carried on tostep 2. MS (apci) m/z=575.3 (M+H).

Step 2: Preparation of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(5-methoxy-2-methylphenyl)pyridazin-3(2H)-one

The tert-butyl4-(4-(5-amino-6-(1-(5-methoxy-2-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylatewas dissolved in 1:1 TFA:DCM (5.0 mL) then stirred 1 h at ambienttemperature. The reaction mixture was concentrated under vacuum thenpurified by C18 reverse phase chromatography (5-95% ACN in H₂O with 0.1%TFA as the gradient eluent) to afford the title compound as a TFA salt.The TFA salt was dissolved in 4:1 DCM:iPrOH (50 mL) and extracted withsaturated NaHCO_(3(aq)) (1×25 mL). The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum tocleanly afford the title compound (102.0 mg, 47% yield). MS (apci)m/z=459.1 (M+H).

Example 38

6-(3-amino-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(5-methoxy-2-methylphenyl)pyridazin-3(2H)-one

A solution of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(5-methoxy-2-methylphenyl)pyridazin-3(2H)-one(Example 37; 187.2 mg, 0.3945 mmol) in 1:1 DCM:MeOH (1.5 mL) was treatedwith formaldehyde (227 μL, 3.02 mmol) and sodium triacetoxyborohydride(128 mg, 0.604 mmol) and stirred 16 h at ambient temperature. Thereaction mixture was concentrated under vacuum then purified by C18reverse phase chromatography (5-95% water-ACN w/0.1% TFA as the gradienteluent). The chromatographic fractions containing the title compoundwere dissolved in 1:1:1 TFA:ACN:water (6 mL) and stirred for 1 h atambient temperature then concentrated under vacuum. The residue wasdiluted with 4:1 DCM:iPrOH (50 mL) and washed with saturatedNaHCO_(3(aq)) (1×25 mL). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated under vacuum to cleanly affordthe title compound (55.0 mg, 77% yield). MS (apci) m/z=473.1 (M+H).

Example 39

6-(3-amino-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(5-methoxy-2-methylphenyl)pyridazin-3(2H)-one2,2,2-trifluoroacetate Salt

A solution of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(5-methoxy-2-methylphenyl)pyridazin-3(2H)-one(Example 37; 22.46 mg, 0.04898 mmol) in DMSO (0.1959 mL) was treatedwith 1-bromo-2-methoxyethane (10.21 mg, 0.07348 mmol) and K₂CO_(3(s))(27.08 mg, 0.19598 mmol). The resulting mixture was stirred overnight at50° C., then cooled to ambient temperature. The reaction was dilutedwith water and extracted with EtOAc. The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum. Thecrude residue was purified by C18 reverse phase chromatography (5-95%Acetonitrile in Water with 0.1% TFA as the gradient eluent) to affordthe title compound (6.5 mg, 26% yield). MS (apci) m/z=517.3 (M+H).

Example 40

6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2-fluoro-5-methoxyphenyl)pyridazin-3(2H)-one Step 1: Preparation of Tert-Butyl4-(4-(5-amino-6-(1-(2-fluoro-5-methoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A suspension of tert-butyl4-(4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate L19; 48.06 mg, 0.1135 mmol),2-(2-fluoro-5-methoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R¹⁴; 117.9 mg, 0.1703 mmol), Pd(PPh₃)₄(13.12 mg, 0.01135mmol), and 2M Na₂CO_(3(aq)) (170.3 μL, 0.3406 mmol) in dioxane (1135 μL)was sparged with Ar_((g)), then sealed and stirred overnight at 90° C.After cooling to ambient temperature, the reaction mixture waspartitioned between EtOAc and water then the aqueous extracts werewashed with EtOAc. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum. Theresulting crude residue was purified by silica chromatography (0-15%MeOH in EtOAc as the gradient eluent) to afford the title compound (15mg, 23% yield). MS (apci) m/z=563.3 (M+H).

Step 2: Preparation of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2-fluoro-5-methoxyphenyl)pyridazin-3(2H)-one

The tert-butyl4-(4-(5-amino-6-(1-(2-fluoro-5-methoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(15 mg, 0.027 mmol) was dissolved in 1:1 TFA:DCM (2.0 mL) then stirredovernight at ambient temperature. The reaction mixture was concentratedunder vacuum then purified by C18 reverse phase chromatography (5-95%ACN in H₂O with 0.1% TFA as the gradient eluent). The chromatographicfractions containing the title compound were combined then neutralizedwith saturated NaHCO_(3(aq)) and extracted with DCM (3x). The organicextracts were then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum to afford the title compound (6.2 mg, 50%yield). MS (apci) m/z=463.2 (M+H).

Example 41

6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2-fluoro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one Step 1: Preparation of tert-butyl4-(4-(5-amino-6-(1-(2-fluoro-3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A suspension of tert-butyl4-(4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate L19; 69.88 mg, 0.1651 mmol),2-(2-fluoro-3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R13; 124.2 mg, 0.2476 mmol), Pd(PPh₃)₄(19.08 mg, 0.01651mmol), and 2M Na₂CO_(3(aq)) (247.6 μL, 0.4952 mmol) in dioxane (1651 μL)was sparged with Ar_((g)), then sealed and stirred overnight at 90° C.After cooling to ambient temperature, the reaction mixture waspartitioned between EtOAc and water then the aqueous extracts werewashed with EtOAc. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum. Theresulting crude residue was purified by silica chromatography (0-15%MeOH in EtOAc as the gradient eluent) to afford the title compound (50mg, 51% yield). MS (apci) m/z=593.3 (M+H).

Step 2: Preparation of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2-fluoro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

The tert-butyl4-(4-(5-amino-6-(1-(2-fluoro-3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(50 mg, 0.084 mmol) was dissolved in 1:1 TFA:DCM (2.0 mL) then stirredovernight at ambient temperature. The reaction mixture was concentratedunder vacuum then purified by C18 reverse phase chromatography (5-95%ACN in H₂O as the gradient eluent). The chromatographic fractionscontaining the title compound were combined then neutralized withsaturated NaHCO_(3(aq)) and extracted with DCM (3x). The organicextracts were then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum to afford the title compound (37.0 mg, 89%yield). MS (apci) m/z=493.2 (M+H).

Example 42

6-(3-amino-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2-fluoro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one2,2,2-trifluoroacetate Salt

A solution of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2-fluoro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 41; 10 mg, 0.020 mmol) in DMSO (81 μL) was treated with1-bromo-2-methoxyethane (6.91 μL, 0.0734762 mmol) and K₂CO_(3(s)) (11mg, 0.081 mmol). The resulting mixture was stirred 3 h at ambienttemperature. The reaction was diluted with water and extracted with DCM.The organic extracts were washed with brine and were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum. Thecrude residue was purified by C18 reverse phase chromatography (25-75%ACN in water with 0.1% TFA as the gradient eluent) to afford the titlecompound (4 mg, 36% yield). MS (apci) m/z=551.2 (M+H).

Example 43

6-(3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one

A solution of 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine(Intermediate L2; 101.7 mg, 0.4003 mmol) in 4:1 dioxane:water (4.0 mL)was treated with2-(3,5-dimethoxyphenyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R18; 260.724 mg, 0.7004 mmol), PdCl₂(dppf).CH₂Cl₂ (32.93mg, 0.04003 mmol), K₂CO_(3(s)) (166.0 mg, 1.201 mmol). The resultingmixture was sparged with Ar_((g)), then sealed and stirred for 16 h at100° C. After cooling to ambient temperature, the reaction mixture wasdiluted with 4:1 DCM:iPrOH (50 mL), and extracted with water (2×25 mL).The organic extracts were dried over anhydrous Na₂SO_(4(s)), filteredand concentrated under vacuum. The resulting crude residue was purifiedby silica chromatography (5-75% DCM/Acetone as the gradient eluent). Thechromatographic fractions containing the title compound were combined,concentrated under vacuum then triturated with DCM (20 mL). Theresulting suspension was filtered and the solids collected were driedunder vacuum to cleanly afford the title compound (90.8 mg, 54% yield).MS (apci) m/z=420.1 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 8.55-8.54 (d,1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.30 (s, 2H), 6.84-6.83(d, 2H), 6.62-6.61 (t, 1H), 3.90 (s, 3H), 3.79 (s, 6H), 2.29 (s, 3H).

Example 44

6-(3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)-4-ethylpyridazin-3(2H)-one2,2,2-trifluoroacetate salt

A suspension of 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine(Intermediate L2; 0.025 g, 0.098 mmol),2-(3,5-dimethoxyphenyl)-4-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R26; 0.042 g, 0.11 mmol), Pd(PPh₃)₄ (0.0085 g, 0.0074mmol) and 2M Na₂CO_(3(aq)) (0.10 mL, 0.21 mmol) in dioxane (1.0 mL) wassparged with Ar_((g)), then sealed and stirred for 8 h at 90° C. Aftercooling to ambient temperature, the reaction mixture was filtered toremove solids. The filtrate was concentrated under vacuum, and theresulting crude residue was purified by C18 reverse phase chromatography(5-95% ACN:water with 0.1% TFA) to afford the title compound as the TFAsalt (0.0056 g, 11% yield). MS (apci) m/z=434.1 (M+H).

The following compounds shown in Table 4 were prepared according themethod used for the synthesis of Example 44 using3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (Intermediate L2)and2-(3,5-dimethoxyphenyl)-4-alkyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediates R25, R27). Reaction progression in each was followed byLCMS and reaction time was adjusted as necessary. All compounds werepurified using a method similar to that used in Example 44 utilizing theappropriate gradient eluent.

TABLE 4 MS (apci) Ex # Structure Name m/z 45

6-(3-amino-6-(1- methyl-1H-pyrazol- 4-yl)pyrazin-2-yl)-2- (3,5-dimethoxyphenyl)-4- propylpyridazin- 3(2H)-one 2,2,2- trifluoroacetatesalt 488.2 (M + H) 46

6-(3-amino-6-(1- methyl-1H-pyrazol- 4-yl)pyrazin-2-yl)-2- (3,5-dimethoxyphenyl)-4- isobutylpyridazin- 3(2H)-one 2,2,2- trifluoroacetatesalt 462.2 (M + H)

Example 47

6-(3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)-4-isopropylpyridazin-3(2H)-one

A solution of 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine(Intermediate L2; 100.0 mg, 0.3936 mmol) in 4:1 dioxane:water (4.0 mL)was treated with2-(3,5-dimethoxyphenyl)-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R23; 173.3 mg, 0.4329 mmol), PdCl₂(dppf).CH₂Cl₂ (32.93 mg,0.04003 mmol), K₂CO_(3(s)) (163.2 mg, 1.181 mmol). The resulting mixturewas sparged with Ar_((g)), then sealed and stirred for 16 h at 100° C.After cooling to ambient temperature, the reaction mixture was dilutedwith 4:1 DCM:iPrOH (50 mL), and extracted with water (2×25 mL). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum. The resulting crude residue was purified bysilica chromatography (5-60% DCM/Acetone as the gradient eluent) tocleanly afford the title compound (27.1 mg, 15% yield). MS (apci)m/z=448.1 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (s, 1H), 8.40 (s, 1H),8.26 (s, 1H), 8.01 (s, 1H), 7.30 (s, 2H), 6.85-6.84 (d, 2H), 6.62-6.61(t, 1H), 3.91 (s, 3H), 3.79 (s, 6H), 3.24-3.17 (m, 1H), 1.30-1.29 (d,6H).

The following compounds shown in Table 5 were prepared according themethod used for the synthesis of Example 47 using3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (Intermediate L2)and2-(3,5-dimethoxyphenyl)-4-alkyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediates R22, R24). Reaction progression in each was followed byLCMS and reaction time was adjusted as necessary. All compounds werepurified using a method similar to that used in Example 47 utilizing theappropriate gradient eluent.

TABLE 5 MS (apci) Ex # Structure Name m/z 48

6-(3-amino-6-(1-methyl- 1H-pyrazol-4-yl)pyrazin- 2-yl)-4-cyclopropyl-2-(3,5- dimethoxyphenyl)pyridazin- 3(2H)-one 446.1 (M + H) 49

6-(3-amino-6-(1-methyl- 1H-pyrazol-4-yl)pyrazin-2-yl)-4-cyclobutyl-2-(3,5- dimethoxyphenyl)pyridazin- 3(2H)-one 460.1(M + H)

Example 50

6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-onedihydrochloride salt Step 1: Preparation of tert-butyl4-(4-(5-amino-6-(1-(3,5-dimethoxyphenyl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of tert-butyl4-(4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate L19; 398 mg, 0.940 mmol),2-(3,5-dimethoxyphenyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one (Intermediate R18; 350 mg, 0.940 mmol), Pd(PPh₃)₄(109 mg,0.0940 mmol), 2M Na₂CO_(3(aq)) (1.41 mL, 0.940 mmol) was suspended indioxane (1.88 mL). The resulting mixture was purged with N_(2(g)) for 6min, then was sealed and stirred for 16 h at 90° C. After cooling toambient temperature, the reaction mixture was diluted with DCM (50 mL)and washed with water (2×15 mL). The organic extracts were dried overanhydrous MgSO_(4(s)), filtered and concentrated under vacuum. The cruderesidue was purified by silica chromatography (1-55% acetone/hexanes asthe gradient eluent) to afford the title compound (425 mg, 77% yield).MS (apci) m/z=589.3 (M+H).

Step 2: Preparation of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-oneDihydrochloride Salt

The tert-butyl4-(4-(5-amino-6-(1-(3,5-dimethoxyphenyl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(420 mg, 0.713 mmol) was dissolved in TFA (2.0 mL) then stirred 2 h atambient temperature. The reaction mixture was concentrated under vacuumthen dissolved in DCM (2 mL) and treated with 2 N HCl in dioxane (5 mL).The resulting suspension was filtered and the solids were rinsed withACN and dried under vacuum to afford the title compound (325 mg, 81%yield). MS (apci) m/z=489.2 (M+H). ¹H NMR (400 MHz, MeOH-d₄) δ 8.59 (d,1H), 8.44 (d, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 6.80 (s, 1H), 6.79 (s,1H), 6.61 (t, 1H), 4.68-4.61 (m, 1H), 3.82 (s, 6H), 3.6-3.56 (m, 2H),3.25-3.2 (m, 2H), 2.3 (s, 3H), 2.35-2.32 (m, 4H).

Example 51

6-(3-amino-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one

A solution of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-onedihydrochloride salt (Example 50; 50 mg, 0.089 mmol) in DMF (1.8 mL) wastreated with 1-bromo-2-methoxyethane (10 μL, 0.11 mmol) and K₂CO_(3(s))(49 mg, 0.36 mmol) under an atmosphere of N_(2(g)). The resultingmixture was stirred overnight at ambient temperature, and thenadditional 1-bromo-2-methoxyethane (20 μL, 0.21 mmol) and K₂CO_(3(s))(98 mg, 0.71 mmol) and the reaction was stirred for an additional periodof 48 h at ambient temperature. The reaction mixture was diluted with 5%iPrOH/DCM (50 mL) and washed with water (10 mL) diluted. The organicextracts were dried over anhydrous MgSO_(4(s)), filtered andconcentrated under vacuum. The crude residue was purified by silicachromatography (2-10% MeOH/DCM as the gradient eluent) to afford thetitle compound (33 mg, 68% yield). MS (apci) m/z=547.3 (M+H). ¹H NMR(400 MHz, CDCl3-d) δ 8.44 (d, 1H), 8.25 (s, 1H), 7.91 (d, 2H), 6.79 (d,2H), 6.51 (t, 1H), 6.48-6.3 (brs, 2H), 4.26-4.18 (m, 1H), 3.81 (s, 6H),3.53 (t, 2H), 3.3 (s, 3H), 3.15-3.09 (m, 2H), 2.63 (d, 2H), 2.3 (s, 3H),2.16-2.1 (m, 2H), 1.61-1.57 (m, 2H).

Example 52

3-(3-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-5-methyl-6-oxopyridazin-1(6H)-yl)-N,4-dimethylbenzamideDihydrochloride Salt Step 1: Preparation of tert-butyl4-(4-(5-amino-6-(1-(5-(methoxycarbonyl)-2-methylphenyl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of tert-butyl4-(4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate L19; 505 mg, 1.19 mmol), methyl4-methyl-3-(5-methyl-6-oxo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-1(6H)-yl)benzoate(Intermediate R19; 550 mg, 1.43 mmol), Pd(PPh₃)₄(107 mg, 0.119 mmol), 2MNa₂CO_(3(aq)) (1.79 mL, 3.58 mmol) was suspended in dioxane (2.39 mL).The resulting mixture was purged with N_(2(g)) for 6 min, then wassealed and stirred overnight at 90° C. After cooling to ambienttemperature, the reaction mixture was diluted with 5% iPrOH/DCM (100 mL)and washed with water (2×20 mL) and brine (20 mL). The organic extractswere dried over anhydrous MgSO_(4(s)), filtered and concentrated undervacuum. The crude residue was purified by silica chromatography (with2-60% acetone/DCM as the gradient eluent) to afford the title compound(782.5 mg, 98% yield). MS (apci) m/z=601.3 (M+H).

Step 2: Preparation of3-(3-(3-amino-6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-5-methyl-6-oxopyridazin-1(6H)-yl)-4-methylbenzoicAcid

A solution of tert-butyl4-(4-(5-amino-6-(1-(5-(methoxycarbonyl)-2-methylphenyl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(780 mg, 1.30 mmol) in 4:1 dioxane:MeOH (6.49 mL) was treated with asolution of LiOH.H₂O (136 mg, 3.25 mmol) in water (1.30 mL). Theresulting mixture was stirred 4 h at ambient temperature thenconcentrated under vacuum. The resulting aqueous slurry was diluted withwater (5 mL) then acidified (pH 2-3) with formic acid. The solid formedwas filtered and dried in vacuo to provide the title compound (650 mg,85% yield). MS (apci) m/z=587.3 (M+H).

Step 3: Preparation of tert-butyl4-(4-(5-amino-6-(5-methyl-1-(2-methyl-5-(methylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A cold (0° C.) suspension of3-(3-(3-amino-6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-5-methyl-6-oxopyridazin-1(6H)-yl)-4-methylbenzoicacid (650 mg, 1.11 mmol) in DMF (22.2 mL) was treated sequentially withHATU (632 mg, 1.66 mmol), 2M CH₃NH₂ in THF (1.11 mL, 2.22 mmol) andDIPEA (1.58 mL, 8.86 mmol). The resulting mixture was stirred 15 min at0° C. then overnight at ambient temperature. The reaction mixture waspoured into ice water and extracted with 5% iPrOH/DCM (3×50 mL). Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered then concentrated under vacuum. The resulting residue waspurified by silica chromatography (5-60% acetone/DCM as the gradienteluent) to afford the title compound (550 mg, 83% yield). MS (apci)m/z=600.3 (M+H).

Step 4: Preparation of3-(3-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-5-methyl-6-oxopyridazin-1(6H)-yl)-N,4-dimethylbenzamideDihydrochloride Salt

A ambient temperature solution of tert-butyl4-(4-(5-amino-6-(5-methyl-1-(2-methyl-5-(methylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(550 mg, 0.917 mmol) in DCM (1 mL) was treated with TFA (2 mL) thenstirred 1 h at ambient temperature before concentrating to dryness undervacuum. The resulting residue was dissolved in DCM (2 mL), treated with4 N HCl in dioxane (2 mL), stirred for 10 min at ambient temperature,and then concentrated to dryness under vacuum. The resulting residue wasresuspended in DCM and concentrated to dryness under vacuum twice thendried under high vacuum to afford the title compound (410 mg, 78%yield). MS (apci) m/z=500.2 (M+H).

Example 53

6-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine(Intermediate L20; 204.8 mg, 0.8061 mmol) in 4:1 dioxane:water (7.5 mL)was treated with2-(3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one (Intermediate R8; 293.4 mg, 0.8192 mmol), PdCl₂(dppf).CH₂Cl₂(61.27 mg, 0.07448 mmol), K₂CO_(3(s)) (308.8 mg, 2.234 mmol). Theresulting mixture was sparged with Ar_((g)), then sealed and stirred for16 h at 100° C. After cooling to ambient temperature, the reactionmixture was diluted with 4:1 DCM:iPrOH (50 mL), and extracted with water(2×25 mL). The organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated under vacuum. The resulting crude residue waspurified by C18 reverse phase chromatography (5-95% water-ACN with 0.1%TFA as the gradient eluent) to afford the title compound as a TFA salt.The TFA salt was dissolved in 4:1 DCM:iPrOH (50 mL) and extracted withsaturated NaHCO_(3(aq)) (1×25 mL). The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum to affordthe title compound along with impurities. The resulting residue wassubjected to further purification by silica chromatography (40-100%DCM-Acetone as the gradient eluent) to cleanly afford the title compound(40.1 mg, 13% yield). MS (apci) m/z=405.1 (M+H). ¹H NMR (400 MHz,DMSO-d₆) δ 8.32-8.31 (d, 1H), 8.28-8.25 (d, 1H), 8.14-8.12 (m, 2H), 7.89(s, 1H), 7.20-7.18 (d, 1H), 6.89 (s, 2H), 6.82-6.81 (d, 2H), 6.61-6.60(t, 1H), 3.85 (s, 3H), 3.78 (s, 6H).

Example 54

6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

Step 1: Preparation of tert-butyl4-(4-(6-amino-5-(1-(3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.A solution of tert-butyl4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate L21; 622.4 mg, 1.474 mmol) in 4:1 dioxane:water (15 mL)was treated with2-(3,5-dimethoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R8; 580.7 mg, 1.621 mmol), PdCl₂(dppf).CH₂Cl₂ (121.2 mg,0.1474 mmol) and K₂CO_(3(s)) (611.0 mg, 4.421 mmol). The resultingmixture was sparged with Ar_((g)), then sealed and stirred 16 h at 100°C. After cooling to ambient temperature, the reaction mixture wasdiluted with 4:1 DCM:iPrOH (250 mL) and washed with water (2×50 mL). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum. The crude residue was purified by silicachromatography (5-95% DCM-Acetone as the gradient eluent) to afford thetitle compound which was immediately carried on to step 2. MS (apci)m/z=574.2 (M+H).

Step 2: Preparation of6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

tert-butyl4-(4-(6-amino-5-(1-(3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylatewas dissolved in 1:1 TFA:DCM (15.0 mL) then stirred 30 min at ambienttemperature. The reaction mixture was concentrated under vacuum thenpurified by C18 reverse phase chromatography (5-95% ACN in H₂O with 0.1%TFA as the gradient eluent) to afford the title compound as a TFA salt.The TFA salt was dissolved in 4:1 DCM:iPrOH (50 mL) and extracted withsaturated NaHCO_(3(aq)) (1×25 mL). The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum tocleanly afford the title compound (415.9 mg, 60% yield). MS (apci)m/z=474.1 (M+H).

Example 55

6-(2-amino-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 54; 134.4 mg, 0.2838 mmol) in 1:1 DCM:MeOH (2.0 mL) was treatedwith formaldehyde (426.5 μL, 5.677 mmol) and sodiumtriacetoxyborohydride (300.8 mg, 1.419 mmol) and then stirred 60 h atambient temperature. The reaction mixture was directly purified bysilica chromatography (1-30% DCM-MeOH w/2% NH₄OH as the gradienteluent). The chromatographic fractions containing the title compoundwere combined then re-purified using C18 reverse phase chromatography(5-95% water-ACN w/0.1% TFA as the gradient eluent) to afford the titlecompound as a TFA salt. The TFA salt was dissolved in 4:1 DCM:iPrOH (50mL) and extracted with saturated NaHCO_(3(aq)) (1×25 mL). The organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum to cleanly afford the title compound (46.9 mg,34% yield). MS (apci) m/z=488.2 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ8.35-8.34 (d, 1H), 8.29 (s, 1H), 8.26 (s, 1H), 8.16-8.15 (d, 1H), 7.91(s, 1H), 7.21-7.18 (d, 1H), 6.91 (s, 2H), 6.82-6.81 (d, 2H), 6.61-6.60(t, 1H), 4.13-4.05 (m, 1H), 3.78 (s, 6H), 2.88-2.85 (m, 2H), 2.22 (s,3H), 2.09-1.91 (m, 6H).

Example 56

6-(2-amino-5-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 54; 54.1 mg, 0.114 mmol) in DMF (1.2 mL) was treated with1-bromo-2-methoxyethane (21.5 μL, 0.228 mmol) and K₂CO_(3(s)) (63.2 mg,0.457 mmol). The resulting mixture was stirred 60 h at ambienttemperature. The reaction mixture was diluted with EtOAc (25 mL) andwashed with water (2×10 mL) and brine (10 mL). The organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated undervacuum. The crude residue was purified by silica chromatography (1-30%DCM-MeOH w/2% NH₄OH as the gradient eluent) to afford the title compound(29.5 mg, 49% yield). MS (apci) m/z=532.2 (M+H).

Example 57

6-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of6-(2-amino-5-bromopyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Intermediate M2; 14.4 mg, 0.0305 mmol) in 4:1 dioxane:water (1.0 mL)was treated with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(6.98 mg, 0.0336 mmol), PdCl₂(dppf).CH₂Cl₂ (2.51 mg, 0.00305 mmol),K₂CO_(3(s)) (12.6 mg, 0.0915 mmol). The resulting mixture was spargedwith Ar_((g)), then sealed and stirred for 16 h at 100° C. After coolingto ambient temperature, the reaction mixture was diluted with EtOAc (25mL), and extracted with water (3×10 mL) and brine (10 mL). The organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated under vacuum. The resulting crude residue was purified bysilica chromatography (5-95% DCM-Acetone as the gradient eluent) toafford the title compound (5.8 mg, 40% yield). MS (apci) m/z=473.0(M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 8.39-8.37 (d, 1H), 8.34-8.33 (d, 1H),8.19-8.18 (d, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.33-7.30 (d, 1H), 7.12(s, 1H), 6.72 (s, 2H), 4.01 (s, 6H), 3.85 (s, 3H).

Example 58

6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-oneStep 1: Preparation of Tert-Butyl4-(4-(6-amino-5-(1-(2,6-dichloro-3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A solution of6-(2-amino-5-bromopyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Intermediate M2; 215.0 mg, 0.4554 mmol) in 4:1 dioxane:water (4.6 mL)was treated with tert-Butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate(180.4 mg, 0.4782 mmol), PdCl₂(dppf).CH₂Cl₂ (37.46 mg, 0.04554 mmol) andK₂CO_(3(s)) (188.8 mg, 1.366 mmol) was sparged with Ar_((g)), thensealed and stirred 6 h at 90° C. After cooling to ambient temperature,the reaction mixture was diluted with 4:1 DCM:iPrOH (50 mL) and washedwith water (2×25 mL). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated under vacuum to afford the titlecompound in sufficient purity for immediate use in step 2. MS (apci)m/z=646.2 [(M+H)+4], 644.2 [(M+H)+2], 642.2 (M+H) with diCl pattern.

Step 2: Preparation of6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

The tert-butyl4-(4-(6-amino-5-(1-(2,6-dichloro-3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylatewas dissolved in 1:1 TFA:DCM (3.0 mL) then stirred 1 h at ambienttemperature. The reaction mixture was concentrated under vacuum thenpurified by C18 reverse phase chromatography (2->75% water-ACN with 0.1%TFA as the gradient eluent) to afford the title compound as a TFA salt.The TFA salt was dissolved in 4:1 DCM:iPrOH (50 mL) and extracted withsaturated NaHCO_(3(aq)) (1×25 mL). The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum tocleanly afford the title compound (172.7 mg, 70% yield). MS (apci)m/z=546.1 [(M+H)+4], 544.2 [(M+H)+2], 542.1 (M+H) with diCl pattern.

Example 59

6-(2-amino-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 58; 50.0 mg, 0.0922 mmol) in MeOH (1.8 mL) was treated withformaldehyde (139 μL, 1.84 mmol) and stirred 15 min at ambienttemperature. The resulting reaction mixture was treated with sodiumtriacetoxyborohydride (78.1 mg, 0.369 mmol) and stirred 16 h at ambienttemperature. The reaction mixture was concentrated under vacuum thenpurified by C18 reverse phase chromatography (5-95% water-ACN w/0.1% TFAas the gradient eluent) to afford the title compound as a TFA salt. TheTFA salt was dissolved in 4:1 DCM:iPrOH (50 mL) and extracted withsaturated NaHCO_(3(aq)) (1×25 mL). The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum tocleanly afford the title compound (24.2 mg, 47% yield). MS (apci)m/z=558.2 [(M+H)+2], 556.2 (M+H) with diCl pattern. H NMR (400 MHz,DMSO-d₆) δ 8.39-8.35 (m, 2H), 8.26-8.24 (m, 1H), 8.21-8.20 (m, 1H), 7.91(s, 1H), 7.33-7.30 (d, 1H), 7.12 (s, 1H), 6.72 (s, 2H), 4.13-4.05 (m,1H), 4.01 (s, 6H), 2.87-2.84 (m, 2H), 2.21 (s, 3H), 2.09-1.79 (m, 6H).

Example 60

6-(2-amino-5-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

A solution of6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Example 58; 17 mg, 0.031 mmol) in DMF (0.31 mL) was treated with1-bromo-2-methoxyethane (3.8 μL, 0.041 mmol) and K₂CO_(3(s)) (6.1 mg,0.045 mmol). The resulting mixture was stirred overnight at ambienttemperature, then filtered through an acrodisc LC 25 mm Syringe filter(with 0.45 μm PVDF Membrane) and the filtrate was purified by C18reverse phase chromatography (5-95% ACN in H₂O with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. Thechromatographic fractions containing the TFA salt of the title compoundwere combined then neutralized with 1M NaOH_((aq)), and extracted withDCM. The organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated under vacuum. The resulting residue waspurified further by silica chromatography (10-90% CHCl₃/10% MeOH/1%NH₄OH in CHCl₃ as the gradient eluent) to afford the title compound (4.0mg, 21% yield). MS (apci) m/z=600.2 (M+H). H NMR (400 MHz, CD₃OD) δ8.30-8.27 (d, 1H), 8.26 (d, 1H), 8.18 (d, 1H), 8.09 (d, 1H), 8.88-8.85(m, 2H), 7.26-7.23 (d, 1H), 7.0 (s, 1H), 4.24-4.16 (m, 1H), 4.00 (s,6H), 3.57-3.54 (t, 3H), 3.34 (s, 3H), 3.15-3.12 (m, 2H), 2.69-2.66 (t,2H), 2.36-2.29 (m, 2H), 2.14-2.08 (m, 4H).

Example 61

3-(3-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-6-oxopyridazin-1(6H)-yl)-N-methylbenzamide Step 1: Preparation of Tert-Butyl4-(4-(6-amino-5-(1-(3-(methylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A solution of3-(3-(2-amino-5-bromopyridin-3-yl)-6-oxopyridazin-1(6H)-yl)-N-methylbenzamide(Intermediate M1; 47.6 mg, 0.119 mmol) in 4:1 dioxane:water (1.2 mL) wastreated with tert-Butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate(49.4 mg, 0.131 mmol), PdCl₂(dppf).CH₂Cl₂ (9.78 mg, 0.0119 mmol) andK₂CO_(3(s)) (49.3 mg, 0.357 mmol). The resulting mixture was spargedwith Ar_((g)), then sealed and stirred 16 h at 100° C. After cooling toambient temperature, the reaction mixture was diluted with 4:1 DCM:iPrOH(25 mL) and washed with water (2×10 mL). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum toafford the title compound which was immediately carried on to step 2. MS(apci) m/z=571.3 (M+H).

Step 2: Preparation of3-(3-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-6-oxopyridazin-1(6H)-yl)-N-methylbenzamide

tert-Butyl4-(4-(6-amino-5-(1-(3-(methylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylatewas dissolved in 1:1 TFA:DCM (1.2 mL) then stirred 30 min at ambienttemperature. The reaction mixture was concentrated under vacuum thenpurified by C18 reverse phase chromatography (5-95% ACN in H₂O with 0.1%TFA as the gradient eluent) to afford the title compound as a TFA salt.The TFA salt was dissolved in 4:1 DCM:iPrOH (50 mL) and extracted withsaturated NaHCO_(3(aq)) (1×25 mL). The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated under vacuum tocleanly afford the title compound (18.8 mg, 34% yield). MS (apci)m/z=471.2 (M+H).

Example 62

3-(3-(2-amino-5-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-6-oxopyridazin-1(6H)-yl)-N-methylbenzamide2,2,2-trifluoroacetate salt

A mixture of3-(3-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-6-oxopyridazin-1(6H)-yl)-N-methylbenzamide(Example 61; 9.88 mg, 0.0210 mmol), 1-bromo-2-methoxyethane (2.17 μL,0.0231 mmol) and K₂CO_(3(s)) (4.35 mg, 0.0315 mmol) in DMSO (0.21 mL)was stirred overnight at ambient temperature. The reaction mixture wasdiluted with DCM and washed with water and brine. The organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered and concentrated invacuo. The crude residue was purified by C18 reverse phasechromatography (5-95% ACN:water with 0.1% TFA) to afford the titlecompound (4.8 mg, 37% yield). MS (apci) m/z=444.1 (M+H).

Example 63

6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3-methylquinolin-7-yl)pyridazin-3(2H)-one bis(2,2,2-trifluoroacetate)

Step 1: Preparation of tert-butyl4-(4-(5-amino-6-(1-(3-methylquinolin-7-yl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:A suspension of tert-butyl4-(4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate L19; 25.640 mg, 0.060570 mmol),2-(3-methylquinolin-7-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(Intermediate R30; 33 mg, 0.1 mmol), Na₂CO₃ (90.855 μL, 0.18171 mmol),and Pd(PPh₃)₄(7.0 mg, 0.006 mmol) in dioxane (605.70 μL, 0.060570 mmol)was sparged with Ar(g), then sealed and stirred 16 h at 90° C. Aftercooling to ambient temperature, the reaction mixture was partitionedbetween EtOAc and water. The organic extracts were washed with brine,dried over anhydrous Na₂SO_(4(s)), filtered and concentrated. Theresidue was purified using silica gel chromatography 0-15% MeOH in EtOActo afford the title compound (12 mg, 0.02 mmol, 34.2% yield). MS (apci)m/z=580.3 (M+H).

Step 2: Preparation of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3-methylquinolin-7-yl)pyridazin-3(2H)-onebis(2,2,2-trifluoroacetate)

tert-butyl4-(4-(5-amino-6-(1-(3-methylquinolin-7-yl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(12 mg, 0.021 mmol) was dissolved in 1:1 TFA/DCM (2.0 mL) and stirred atambient temperature for 6 h. The reaction mixture was concentrated undervacuum, and then treated with 2 mL MeOH. The mixture was concentratedunder vacuum to afford the title compound as the TFA salt (9.1 mg, 0.019mmol, 92% yield) MS (apci) m/z=480.2 (M+H).

Example 646-(3-amino-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3-methylquinolin-7-yl)pyridazin-3(2H)-one

A solution6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3-methylquinolin-7-yl)pyridazin-3(2H)-onebis(2,2,2-trifluoroacetate) (Example 63; 8 mg, 0.02 mmol) in DMSO (556μL) was treated with K₂CO_(3(s)) (4.6 mg, 0.03 mmol). The mixture wascooled to 0° C. in an ice water bath, and 1-bromo-2-methoxyethane (2 μL,0.02 mmol) was added. The resulting mixture was warmed to ambienttemperature and stirred for 50 h. The reaction was diluted with waterand extracted with DCM. The organic extracts were washed with brine,dried over anhydrous Na₂SO_(4(s)), filtered and concentrated undervacuum. The crude residue was purified by silica gel chromatography(0-100% Acetone in DCM as the gradient eluent followed by 10% MeOH inDCM) to afford the title compound (1.8 mg, 20% yield). MS (apci)m/z=538.2 (M+H).

Example 65

(S)-6-(3-amino-6-(1-((4,5,5-trimethylmorpholin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate

A solution of(S)-6-(3-amino-6-(1-((5,5-dimethylmorpholin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one(29 mg, 0.0559 mmol) (Example 27; 29 mg, 0.06 mmol) in MeOH (0.5 mL) wastreated with formaldehyde (12.6 μL, 0.168 mmol) and stirred for 15 minat ambient temperature. The resulting reaction mixture was treated withsodium triacetoxyborohydride (35.6 mg, 0.168 mmol) and stirred 30minutes at ambient temperature. The reaction mixture was concentratedunder vacuum and then purified by C18 reverse phase chromatography(5-95% water-ACN w/0.1% TFA as the gradient eluent) to afford the titlecompound as a TFA salt (22 mg, 74% yield). MS (apci) m/z=533.2 (M+H).

Example 66

6-(3-amino-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one

Step 1: A mixture of tert-butyl4-(4-(5-amino-6-bromopyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate L19; 0.225 g, 0.532 mmol),2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one (Intermediate R16; 0.234 g, 0.532 mmol), Pd(PPh₃)₄(0.0461 g,0.0399 mmol) and 2 M solution of Na₂CO₃ (0.558 mL, 1.12 mmol) in dioxane(3 mL) was stirred at 90° C. for 8 hours. The mixture was then filteredthrough filter paper and the filtrate was concentrated. The residue waspurified on a silica column using Hexanes:EtOAc (10-90%) to givetert-butyl4-(4-(5-amino-6-(1-(2,6-dichloro-3,5-dimethoxyphenyl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.213 g, 0.324 mmol, 60.9% yield). MS (apci) m/z=657.2 (M+H).

Step 2: A mixture of tert-butyl4-(4-(5-amino-6-(1-(2,6-dichloro-3,5-dimethoxyphenyl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.213 g, 0.324 mmol) in TFA (1.5 ml) and DCM (1.62 ml) was stirred atroom temperature for 30 min and then concentrated. The residue waspartitioned between DCM and aqueous saturated Na₂CO₃. The combinedorganic extracts were washed with brine, dried over Na₂SO₄ andconcentrated to give6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one(0.157 g, 0.282 mmol, 86.9% yield). MS (apci) m/z=557.2 (M+H).

Step 3: 1-bromo-2-methoxyethane (0.009365 ml, 0.09965 mmol) was added to6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one(0.0505 g, 0.09059 mmol) and K₂CO₃ (0.03756 g, 0.2718 mmol) in DMF(0.9059 ml) at room temperature. The reaction mixture was stirred for 3days. The mixture was taken up in DCM and extracted with water. Thecombined organic extracts were washed with water and brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified by C18reverse phase chromatography (5-95% ACN:water with 0.1% TFA). Theisolated product was taken up in DCM and washed with aqueous saturatedNa₂CO₃ and brine, dried over Na₂SO₄, filtered and concentrated toprovide6-(3-amino-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one(0.0145 g, 0.02356 mmol, 26.00% yield). MS (apci) m/z=615.2 (M+H).

Example 67

6-(3-amino-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3,5-dimethoxy-2-methylphenyl)pyridazin-3(2H)-one

Step 1: To a solution of 6-chloro-2-(3,5-dimethoxyphenyl)pyridazin-3(2H)-one (0.505 g, 1.89 mmol) in acetonitrile (18.9 mL, 1.89 mmol) wasadded 1-bromopyrrolidine-2,5-dione (0.337 g, 1.89 mmol) at 0° C. Thereaction mixture was warmed to ambient temperature after 10 minutes andstirred for 2.5 hours. The mixture was partitioned between EtOAc andwater. The combined organic phases were washed with water and brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography (10-90% EtOAc in hexanes) to yield2-(2-bromo-3,5-dimethoxyphenyl)-6-chloropyridazin-3(2H)-one (0.611 g,1.77 mmol, 93.4% yield). MS (apci) m/z=346.9 [(M+H)+2], 344.9 (M+H) withBr pattern.

Step 2: To a solution of2-(2-bromo-3,5-dimethoxyphenyl)-6-chloropyridazin-3(2H)-one (0.308 g,0.891 mmol) in THF (5.94 ml, 0.891 mmol) was added methylzinc(II)chloride (0.446 mL, 0.891 mmol) and the mixture was sparged with Ar for15 min. Bis(tri-t-butylphosphine) Pd(0) (0.0455 g, 0.0891 mmol) wasadded and the reaction mixture was heated to 60° C. under N2 for 3hours. The mixture was concentrated in vacuo and the concentrate wassuspended in DCM, washed with water and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography (10-90% EtOAc in hexanes) to yield6-chloro-2-(3,5-dimethoxy-2-methylphenyl)pyridazin-3(2H)-one (0.109 g,0.388 mmol, 43.6% yield). MS (apci) m/z=281.0 (M+H).

Step 3: To a solution of6-chloro-2-(3,5-dimethoxy-2-methylphenyl)pyridazin-3(2H)-one (0.031 g,0.11 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.042 g,0.17 mmol) in 1,4-dioxane (1.1 mL, 0.11 mmol) was added potassiumacetate (0.033 g, 0.33 mmol) and the mixture was sparged with Ar for 5mins. 2-(Dicyclohexylphosphino)-2,4,6-Triisopropylbiphenyl (0.0079 g,0.017 mmol) and Palladium(II) acetate (0.0025 g, 0.011 mmol) were thenadded sequentially and the reaction mixture was sparged with Ar. Thereaction vessel was sealed and the reaction mixture was heated to 100°C. for 1 hr. The mixture was partitioned between DCM and water. Thecombined organic extracts were washed with water and brine, dried overNa₂SO₄, filtered and concentrated in vacuo to provide2-(3,5-dimethoxy-2-methylphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(0.041 g, 0.11 mmol, assumed quantitative yield).

Step 4: To a solution of3-bromo-5-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-amine(Intermediate L22; 0.034 g, 0.089 mmol) and2-(3,5-dimethoxy-2-methylphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(0.040 g, 0.11 mmol) in 1,4-dioxane (0.89 mL, 0.089 mmol) was addedsodium carbonate (0.13 mL, 0.27 mmol) and the reaction mixture wassparged with Ar for 5 mins. Tetrakis(triphenylphosphine)Pd(0) (0.0082 g,0.0071 mmol) was added and the reaction mixture was sparged with Ar. Themixture was sealed and heated to 100° C. for 2 hours with stirring. Themixture was cooled to ambient temperature and purified by reverse phasechromatography (5-95% ACN:water with 0.1% TFA) to provide the titlecompound (0.020 g, 0.037 mmol, 41% yield) as a yellow powder. MS (apci)m/z=547.3 (M+H).

Example 68

6-(3-amino-6-(1-(2-oxo-2-(piperidin-1-yl)ethyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

To a solution of6-(3-amino-6-bromopyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Intermediate M3; 0.025 g, 0.053 mmol) in 1,4-dioxane (0.53 mL, 0.053mmol) was added sodium carbonate (0.079 mL, 0.16 mmol) and1-(piperidin-1-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanone(0.020 g, 0.063 mmol) and the reaction mixture was sparged with Ar for 5mins. Tetrakis(triphenylphosphine)palladium(0) (0.0049 g, 0.0042 mmol)was added and the reaction mixture was sparged with Ar. The reaction wassealed, heated to 100° C. and stirred for 2.5 hrs. The reaction wascooled to ambient temperature and purified by reverse phasechromatography (5-95% ACN:water with 0.1% TFA) to provide the titlecompound (0.020 g, 0.037 mmol, 41% yield) as a yellow powder. MS (apci)m/z=589.2 [(M+H)+4], 587.2 [(M+H)+2], 585.1 (M+H) with di Cl pattern.

Example 69

6-(3-amino-6-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

To a solution of6-(3-amino-6-bromopyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Intermediate M3; 0.026 g, 0.055 mmol) in 1,4-dioxane (0.55 mL, 0.053mmol) was added sodium carbonate (0.079 mL, 0.16 mmol) andN,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine(0.019 g, 0.071 mmol) and the reaction mixture was sparged with Ar for 5mins. Tetrakis(triphenylphosphine)Palladium(0) (0.0051 g, 0.0044 mmol)was added and the reaction mixture was sparged with Ar. The reaction wassealed, heated to 100° C. and stirred for 2.5 hrs. The mixture wascooled to ambient temperature and purified by flash chromatography (1-9%MeOH in DCM) to yield the title compound (0.018 g, 0.034 mmol, 62%yield) as a yellow powder. MS (apci) m/z=535.1 [(M+H)+4], 533.1[(M+H)+2], 531.2 (M+H) with di Cl pattern. ¹H NMR (DMSO) δ 8.71 (d, 1H),8.48 (s, 1H), 8.32 (d, 1H), 8.00 (d, 1H), 7.30 (d, 1H), 7.10 (s, 1H),7.03 (br s, 2H, NH₂), 4.20 (t, 2H), 3.99 (s, 6H), 2.66 (t, 2H), 2.15 (s,6H).

The following compounds shown in Table 6 were prepared according themethod used for the synthesis of Example 69 using6-(3-amino-6-bromopyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one(Intermediate M3; 0.026 g, 0.055 mmol). Reaction progression in each wasfollowed by LCMS and reaction time was adjusted as necessary. Allcompounds were purified using a method similar to that used in eitherExample 68 or Example 69 utilizing the appropriate gradient eluent.Table 6

TABLE 6 MS (apci) Ex. # Structure Name m/z 70

6-(3-amino-6-(1-methyl- 3-(trifluoromethyl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyridazin- 3(2H)-one 542.1 (M +H) 71

6-(3-amino-6-(1,3,5- trimethyl-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyridazin- 3(2H)-one 502.1 (M + H) 72

6-(3-amino-6-(1-(1- hydroxy-2- methylpropan-2-yl)-1H-pyrazol-4-yl)pyrazin-2- yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyridazin- 3(2H)-one 532.1 (M + H) 73

6-(3-amino-6-(1- isopropyl-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyridazin- 3(2H)-one 502.1 (M + H) 74

6-(3-amino-6-(1- cyclopropyl-1H-pyrazol- 4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyridazin- 3(2H)-one 500.1 (M + H) 75

6-(3-amino-6-(1- (azetidin-3-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyridazin- 3(2H)-one 515.1 (M +H)

Example 76

6-(3-amino-6-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one

To a solution of6-(3-amino-6-bromopyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one(Intermediate M4; 0.069 g, 0.14 mmol) in 1,4-dioxane (1.42 ml, 0.142mmol) was added sodium carbonate (0.21 mL, 0.43 mmol) andN,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine(0.0488 g, 0.184 mmol) and the reaction mixture was sparged with Ar for5 mins. Tetrakis(Triphenylphosphine)Palladium(0) (0.0131 g, 0.0113 mmol)was added and the reaction mixture was sparged with Ar. The reaction wassealed, heated to 100° C. and stirred for 2 hrs. The mixture was cooledto ambient temperature and purified by flash chromatography (1-9% MeOHin DCM) to yield the title compound (0.0256 g, 0.0469 mmol, 33.1% yield)as a yellow powder. MS (apci) m/z=549.1 [(M+H)+4], 547.1 [(M+H)+2],545.2 (M+H) with di Cl pattern. ¹H NMR (CDCl₃) δ 8.48 (m, 1H), 8.27 (s,1H), 7.96 (d, 1H), 7.94 (d, 1H), 6.71 (s, 1H), 6.20 (br s, 2H, NH₂),4.30 (t, 2H), 3.99 (s, 6H), 2.83 (t, 2H), 2.41 (d, 3H), 2.31 (s, 6H).

Example 77

6-(3-amino-6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one

Step 1: To a solution of6-(3-amino-6-bromopyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one(Intermediate M4; 0.120 g, 0.246 mmol) in 1,4-dioxane (2.46 ml, 0.246mmol) was added sodium carbonate (0.370 mL, 0.739 mmol) and tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(0.103 g, 0.296 mmol) and the reaction mixture was sparged with Ar.tetrakis(triphenylphosphine)palladium(0) (0.0228 g, 0.0197 mmol) wasadded and the reaction mixture was sparged with Ar. The reaction wassealed, heated to 100° C. and stirred for 2 hrs. The mixture was cooledto ambient temperature and purified by flash chromatography (1-5% MeOHin DCM) to yield the title compound (0.0256 g, 0.0469 mmol, 33.1% yield)as a yellow powder. MS (apci) m/z=633.2 [(M+H)+4], 631.2 [(M+H)+2],629.2 (M+H) with di Cl pattern.

Step 2: 2,2,2-Trifluoroacetic acid (1.0 ml, 0.10 mmol) was added to asolution of tert-butyl3-(4-(5-amino-6-(1-(2,6-dichloro-3,5-dimethoxyphenyl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(0.065 g, 0.10 mmol) in dichloromethane (1.0 mL, 0.10 mmol) at ambienttemperature for 3.5 hrs. The mixture was partitioned between DCM andaqueous saturated Na₂CO₃. The combined organic extracts were washed withbrine and concentrated to provide the title compound (0.045 g, 0.085mmol, 82% yield) as a yellow solid. MS (apci) m/z=533.1 [(M+H)+4], 531.1[(M+H)+2], 529.2 (M+H) with di Cl pattern.

Example 78

6-(3-amino-6-(1-(1-(2-methoxyethyl)azetidin-3-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one

1-Bromo-2-methoxyethane (0.002915 mL, 0.03138 mmol) was added to a vialcontaining6-(3-amino-6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one(Example 77; 0.0151 g, 0.02852 mmol) and potassium carbonate (0.005913g, 0.04279 mmol) in DMF (0.5705 mL, 0.02852 mmol) at ambienttemperature. The mixture was stirred in sealed vial for 48 hrs. Themixture was partitioned between DCM and water. The combined organicextracts were washed with water and brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by reverse phasechromatography (5-95% ACN:water with 0.1% TFA) to yield the titlecompound (0.0051 g, 0.008681 mmol, 30.44% yield) as a yellow solid. MS(apci) m/z=591.1 [(M+H)+4], 589.1 [(M+H)+2], 587.1 (M+H) with di Clpattern.

Example 79

6-(3-amino-6-(1-(1-(2-ethoxyethyl)azetidin-3-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one

1-Bromo-2-ethoxyethane (0.003632 mL, 0.03221 mmol) was added to a vialcontaining6-(3-amino-6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one(Example 77; 0.0155 g, 0.02928 mmol) and potassium carbonate (0.006070g, 0.04392 mmol) in DMF (0.9760 mL, 0.02928 mmol) at ambienttemperature. The reaction stirred in a sealed vial for 15 hrs. Themixture was partitioned between DCM and water. The combined organicswere washed with water and brine, dried over Na₂SO₄, and concentrated invacuo. The mixture was purified by reverse phase chromatography (5-95%ACN:water with 0.1% TFA) to yield the title compound (0.0042 g, 0.006983mmol, 23.85% yield) as a yellow solid. MS (apci) m/z=605.2 [(M+H)+4],603.2 [(M+H)+2], 601.2 (M+H) with di Cl pattern.

Example 80

3-(3-(3-amino-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-5-methyl-6-oxopyridazin-1(6H)-yl)-N,4-dimethylbenzamide

To a solution of the3-(3-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-5-methyl-6-oxopyridazin-1(6H)-yl)-N,4-dimethylbenzamidedihydrochloride (50 mg, 0.087 mmol) in N,N-dimethylformamide (1747 μL,0.087 mmol) at 0° C. under a nitrogen atmosphere was sequentially addedK₂CO₃ (49 mg, 0.35 mmol) and 1-bromo-2-methoxyethane (10 μL, 0.11 mmol).The mixture was stirred at RT overnight. The resulting mixture wasdiluted with 5% IPA/DCM (50 mL) and washed with water (10 mL). Theorganic layer was separated, dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by flash chromatography on silica gel(Redi Sep 24 g) eluting with 2-20% MeOH/DCM with 2% NH₄OH to provide3-(3-(3-amino-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-5-methyl-6-oxopyridazin-1(6H)-yl)-N,4-dimethylbenzamide(25 mg, 51% yield) as a solid. LCMS (APCI+) m/z 558.2 (M+1), Retentiontime=1.751 min.

Example 81

6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-one Dihydrochloride

Step 1: A glass pressure tube was charged with Intermediate R¹⁸ [crude2-(3,5-dimethoxyphenyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one](660 mg, 1.77 mmol), Intermediate L21 [tert-butyl4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate](749 mg, 1.77 mmol), Pd(Ph₃P)₄ (205 mg, 0.177 mmol), sodium carbonate 2Min water (2660 μL, 5.32 mmol) and 1,4-dioxane (3546 μL, 1.77 mmol). Themixture was purged with N₂ for 6 minutes. The tube was sealed with aTeflon screw cap and heated at 90° C. with vigorous stirring for 16hours. The mixture was cooled to RT, diluted with DCM (100 mL) andwashed with water. The organic phase was separated, dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (Redi Sep 40 g) eluting with 1-55%acetone/hexanes (20 CV) to provide tert-butyl4-(4-(6-amino-5-(1-(3,5-dimethoxyphenyl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(780 mg, 75% yield) as a solid. LCMS (APC1+) m/z 588.2 (M+1), retentiontime=2.528 min.

Step 2: Neat TFA (3 mL) was added to the tert-butyl4-(4-(6-amino-5-(1-(3,5-dimethoxyphenyl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(600 mg, 1.02 mmol). The mixture was stirred at RT for 1 hour. The TFAwas removed in vacuo and the residue was treated with 4N HCl in dioxane(5 mL). The mixture was stirred at RT for 15 minutes and the solvent wasremoved in vacuo. The residue was evaporated from CH₃CN and dried underhigh vacuum to provide6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3,5-dimethoxyphenyl)-4-methylpyridazin-3(2H)-onedihydrochloride (425 mg, 74.3% yield) as a solid. LCMS (APCI+) m/z 488.2(M+1); Retention time=2.261 min.

Example 82

6-(3-amino-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-difluoro-3,5-dimethoxyphenyl)pyridazin-3(2H)-one

Step 1: A mixture of Intermediate L19 (228 mg, 0.538 mmol), IntermediateR²⁹ (212 mg, 0.538 mmol), K₂CO₃ (2M, 807 μL, 1.61 mmol) and Pd(Ph₃P)₄(31.1 mg, 0.027 mmol) in dioxane (2.7 mL, 0.54 mmol) was sparged withnitrogen and heated at 80° C. for 3 h. The reaction mixture waspartitioned between ethyl acetate and water. The aqueous layer wasextracted with EtOAc. The combined organic layers were dried andconcentrated. The residue was purified by flash chromatography elutingwith a hexanes/EtOAc gradient (0-100%) to provide tert-butyl4-(4-(5-amino-6-(1-(2,6-difluoro-3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.LCMS (APCI+) m/z 611.2 (M+1); Retention time=3.35 min.

Step 2: tert-butyl4-(4-(5-amino-6-(1-(2,6-difluoro-3,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylatewas stirred in a solution of 1:1 DCM/TFA (10 mL) for 1 h. The mixturewas concentrated at 50° C. The residue was diluted with MeOH (5 mL) and6N HCl/iPrOH (5 mL) was added. The mixture was concentrated to provide6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-difluoro-3,5-dimethoxyphenyl)pyridazin-3(2H)-onehydrochloride salt as a white solid. LCMS (APCI+) m/z 511.2 (M+1);Retention time=2.35 min.

Step 3: To a suspension of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2,6-difluoro-3,5-dimethoxyphenyl)pyridazin-3(2H)-onehydrochloride salt (31.8 mg, 0.062 mmol) and K₂CO₃ (43.0 mg, 0.312 mmol)in DMF (1246 μL, 0.062 mmol) was added 2-bromoethyl methyl ether (7.01μL, 0.075 mmol) and the resulting mixture was stirred at RT for 1 d. Thecrude reaction mixture was loaded onto a silica column equilibrated withhexanes and eluted with hexanes>DCM>20% MeOH/DCM to provide the titlecompound (18 mg, 0.031 mmol, 50.8%). LCMS (APCI+) m/z=569.2; retentiontime 2.40 min.

Example 83

6-(3-amino-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2-chloro-6-fluoro-3-methoxyphenyl)pyridazin-3(2H)-one

Step 1: A mixture of Intermediate L19 (262 mg, 0.620 mmol), IntermediateR²⁸ (236 mg, 0.620 mmol), K₂CO₃ (2 M, 930 μL, 1.86 mmol) and Pd(Ph₃P)₄(35.8 mg, 0.031 mmol) in dioxane (3.1 mL, 0.62 mmol) was sparged withnitrogen and heated at 80° C. for 3 h. The reaction was partitionedbetween ethyl acetate and water. The combined organic layers were driedover Na₂SO₄, filtered and concentrated. The residue was purified byflash chromatography eluting with a hexane/Ethyl acetate gradient of0-100% to provide tert-butyl4-(4-(5-amino-6-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.LCMS (APCI+) m/z=597.2 (100%), 599.2(40%); retention time 3.38 min.

Step 2: tert-butyl4-(4-(5-amino-6-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylatewas treated with 1:1 DCM/TFA (20 mL) for 1 h. The solution wasconcentrated and 5 mL of 6N HCl/iPrOH and 5 mL of MeOH was added. Themixture was stirred for 1 h to form a white slurry and the suspensionwas concentrated. LCMS (APCI+) m/z=497.0 (100%), 499.0 (40%); retentiontime 2.33 min.

Step 3: To a suspension of6-(3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2-chloro-6-fluoro-3-methoxyphenyl)pyridazin-3(2H)-one(25.3 mg, 0.051 mmol) and K₂CO₃ (35.2 mg, 0.255 mmol) in DMF (1.0 ml,0.051 mmol) was added 2-bromoethyl methyl ether (5.74 al, 0.06 mmol) andthe resulting mixture was stirred at RT for 1 d. The crude reactionmixture was loaded onto a silica column equilibrated with hexanes andeluted with hexanes>DCM>20% MeOH/DCM to provide the title compound (12mg, 0.021 mmol, 42%). LCMS (APCI+) m/z=555.2; retention time 2.388.

Biological Activity Example A Enzyme Assay

FGFR1, 2 and 3 kinase activity was measured by the InvitrogenLanthaScreen™ Assay technology which directly measures the amount ofsubstrate phosphorylation by TR-FRET using a fluorescein-labeled peptideand Europium-labeled antibody.

To measure FGFR1 kinase activity, 200 pM His-tagged recombinant humanFGFR1 catalytic domain (amino acids 308-731) (Life Technologies Cat. No.PR4660A) was incubated with 100 nM Alexa Fluor® 647-Poly-GT PeptideSubstrate (Life Technologies Cat. No. PV5836) and ATP in the presence ofMg^(++,) along with test compound in a buffer consisting of 250 mMHEPES, 25 mM MgCl₂, 0.05% TritonX-100, pH 7.5, and 2% DMSO. Compoundswere typically prepared in a threefold serial dilution in DMSO and addedto the assay to give the appropriate final concentration. After 20minutes incubation at 22° C., an equal volume of 2 nM LanthaScreen®Eu-PY20 Antibody (Life Technologies Cat. No. PV5691) and EDTA were addedto quench the kinase reaction and start the detection reaction. After anadditional 60 minute incubation at 22° C., the reaction was measuredusing a PerkinElmer EnVision multimode plate reader via TR-FRET dualwavelength detection, and the percent of control (POC) calculated usinga ratiometric emission factor. 100 POC is determined using no testcompound and 0 POC is determined using no enzyme. The POC values werefit to a 4 parameter logistic curve and the IC₅₀ value is point wherethe curve crosses 50 POC.

To measure FGFR2 kinase activity: 200 pM His-tagged recombinant humanFGFR2 cytoplasmic domain (amino acids 403-822), (Life Technologies Cat.No. PR5332A); 20 minutes incubation at 22° C., 60 minute detectionincubation at 22° C.

To measure FGFR3 kinase activity: 750 pM N-terminal GST-HIS6 fusionprotein with a 3C cleavage site recombinant human FGFR3 (amino acidsR397-T806) (ProQinase Cat. No. 1068-0000-1); 10 minutes incubation at22° C., 60 minute detection incubation at 22° C.

The averaged IC₅₀ values for the compounds tested in this assay areprovided in Table F.

TABLE F IC₅₀'s of compounds tested in the assay of Example A FGFR1 EnzFRET FGFR2 Enz FRET FGFR3 Enz FRET IC50 (nM) IC50 (nM) IC50 (nM) Ex. #[AVERAGE] [AVERAGE] [AVERAGE]  1 18.1 3.4 4.3  2 259.6 60.4 69.1  34749.7 1963.4 4121.7  4 15.4 2.8 2.4  5 17.0 3.2 2.9  6 22.2 6.4 11.2  714.5 6.5 10.7  8 N/A 120.0 176.7  9 N/A 1055.6 4251.3 10 N/A 214.7 293.011 143.2 23.7 22.6 12 838.2 150.6 191.5 13 316.3 64.3 15.1 14 6.3 1.61.7 15 17.4 3.7 7.0 16 22.8 5.6 10.6 17 79.2 10.2 3.8 18 47.7 8.5 8.7 1915.1 2.8 2.2 20 399.9 39.8 61.5 21 39.1 7.5 4.9 22 192.5 21.1 6.7 23 3.85.5 2.8 24 15.0 1.8 4.0 25 51.1 6.6 11.8 26 8.6 2.2 4.3 27 19.0 1.9 8.228 17.0 2.3 4.7 29 22.0 3.7 7.1 30 14.1 2.9 6.5 31 7.7 1.4 3.9 32 9.21.3 1.8 33 11.6 1.8 4.5 34 38.4 3.7 13.4 35 15.4 3.2 4.8 36 62.8 6.221.3 37 56.0 19.2 23.5 38 91.5 16.8 21.1 39 141.8 9.4 28.6 40 49.7 2.910.2 41 3.0 0.8 3.2 42 6.3 1.4 8.6 43 7.0 1.6 1.7 44 7.1 1.4 6.2 451561.6 825.7 1086.6 46 3101.2 1231.5 3604.1 47 5.6 1.6 1.5 48 3.1 1.01.4 49 6.0 1.3 2.1 50 3.5 0.9 1.8 51 4.0 0.6 1.0 52 26.8 5.0 42.5 53193.4 72.3 35.6 54 29.6 10.9 10.1 55 31.4 6.3 19.9 56 43.3 7.5 5.7 5713.8 5.8 6.2 58 4.4 2.4 0.7 59 5.0 6.6 10.6 60 11.6 1.5 10.3 61 98.224.1 13.7 62 231.3 31.2 166.2 63 14.0 16.0 53.5 64 61.4 42.1 213.7 658.9 2.9 35.0 66 5.6 7.8 3.9 67 9.1 6.5 13.3 68 9.8 11.1 6.4 69 7.2 9.69.6 70 30.9 54.4 30.8 71 26.5 38.8 45.1 72 7.3 9.3 5.2 73 7.2 10.6 6.074 5.8 9.5 6.1 75 8.0 11.3 10.2 76 10.6 3.85 7.1 77 16.1 6.2 12.4 78 9.83.7 6.9 79 17.3 6.3 10.7 80 57.0 16.3 50.6 81 3.6 1.1 11.4 82 2.4 3.12.2 83 6.9 16.6 26.5 N/A = Not available

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications,websites, and other references cited herein are hereby expresslyincorporated herein in their entireties by reference.

1.-27. (canceled)
 28. A method for treating cancer in a patient in needthereof, the method comprising administering to the patient atherapeutically effective amount of a compound of general Formula I:

and pharmaceutically acceptable salts thereof, wherein: X is N or CH;Ring A is a 5-membered heteroaryl ring having 1-2 ring nitrogen atoms; zis 1, 2 or 3; each R¹ is independently selected from the groupconsisting of: (a) hydrogen; (b) C1-C6 alkyl optionally substituted with1-3 fluoros, (c) hydroxy(C1-C6 alkyl)- optionally substituted with 1-3fluoros, (d) dihydroxy(C1-C6 alkyl)- optionally substituted with 1-3fluoros, (e) cyano(C1-C6 alkyl)-, (f) R^(a)R^(b)N(C1-C6 alkyl)-, (g)(C1-C3 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros, (h)(C3-C6 cycloalkyl)(CH₂)_(n)— where n is 0-3 and said cycloalkyl isoptionally substituted with CN, OH, R^(a)R^(b)N—, (1-3C)alkyl, or(1-3C)alkoxy; (i) hetCyc¹(CH₂)_(m)— where m is 0-3, (j)hetCyc²(CH₂)_(p)— where p is 0 or 1, (k) hetAr¹(CH₂)_(q)— where q is 1or 2, (l) halogen, and (m) hetCyc¹C(═O)CH₂—; hetCyc¹ is a 4-7 memberedsaturated heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, wherein said heterocyclic ring is optionallysubstituted with one or more substituents independently selected fromthe group consisting of fluoro, HO, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substitutedwith 1-3 fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6alkyl)-, R^(c)R^(d)N- and (C1-C6 alkyl)C(═O)—; hetCyc² is a 7-10membered heterospirocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein said heterospirocyclic ringis optionally substituted with one or more substituents independentlyselected from the group consisting of C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionallysubstituted with 1-3 fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-,hydroxy(C1-C6 alkyl)-, R^(c)R^(d)N- and (C1-C6 alkyl)C(═O)—; hetAr¹ is a6-membered heteroaryl ring having 1-2 ring nitrogen atoms, wherein saidring is optionally substituted with one or more substituentsindependently selected from C1-C6 alkyl and halogen; R² is Ar¹ orhetAr²; Ar¹ is phenyl substituted with one or more groups independentlyselected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (cyclopropyl)C(═O)NH— and(cyclopropyl)NHC(═O)—, wherein each of said C1-C3 alkyl and C1-C3 alkoxyportions is optionally substituted with 1-3 fluoros; hetAr² is a 6-10membered heteroaryl ring having 1-2 ring nitrogen atoms, wherein saidring is optionally substituted with one or more groups independentlyselected from halogen, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—,(C1-C3 alkyl)C(═O)NH—, (C3-C4 cycloalkyl)C(═O)NH— and (C3-C4cycloalkyl)NHC(═O)—, wherein each of said C1-C3 alkyl and C1-C3 alkoxyportions is optionally substituted with 1-3 fluoros; R³ is H, C1-C4alkyl or (C3-C4)cycloalkyl; and R^(a), R^(b), R^(c) and R^(d) areindependently hydrogen or C1-C6 alkyl optionally substituted with F, OHor C1-C6 alkoxy. 29.-30. (canceled)
 31. A method of treating anFGFR-associated cancer in a patient, the method comprising: determiningif the cancer in the patient is an FGFR-associated cancer; andadministering to a patient determined to have an FGFR-associated cancera therapeutically effective amount of a compound of general Formula I:

and pharmaceutically acceptable salts thereof, wherein: X is N or CH;Ring A is a 5-membered heteroaryl ring having 1-2 ring nitrogen atoms; zis 1, 2 or 3; each R¹ is independently selected from the groupconsisting of: (a) hydrogen; (b) C1-C6 alkyl optionally substituted with1-3 fluoros, (c) hydroxy(C1-C6 alkyl)- optionally substituted with 1-3fluoros, (d) dihydroxy(C1-C6 alkyl)- optionally substituted with 1-3fluoros, (e) cyano(C1-C6 alkyl)-, (f) R^(a)R^(b)N(C1-C6 alkyl)-, (g)(C1-C3 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros, (h)(C3-C6 cycloalkyl)(CH₂)_(n)— where n is 0-3 and said cycloalkyl isoptionally substituted with CN, OH, R^(a)R^(b)N—, (1-3C)alkyl, or(1-3C)alkoxy; (i) hetCyc¹(CH₂)_(m)— where m is 0-3, (j)hetCyc²(CH₂)_(p)— where p is 0 or 1, (k) hetAr¹(CH₂)_(q)— where q is 1or 2, (l) halogen, and (m) hetCyc¹C(═O)CH₂—; hetCyc¹ is a 4-7 memberedsaturated heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, wherein said heterocyclic ring is optionallysubstituted with one or more substituents independently selected fromthe group consisting of fluoro, HO, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substitutedwith 1-3 fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6alkyl)-, R^(c)R^(d)N- and (C1-C6 alkyl)C(═O)—; hetCyc² is a 7-10membered heterospirocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein said heterospirocyclic ringis optionally substituted with one or more substituents independentlyselected from the group consisting of C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionallysubstituted with 1-3 fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-,hydroxy(C1-C6 alkyl)-, R^(c)R^(d)N- and (C1-C6 alkyl)C(═O)—; hetAr¹ is a6-membered heteroaryl ring having 1-2 ring nitrogen atoms, wherein saidring is optionally substituted with one or more substituentsindependently selected from C1-C6 alkyl and halogen; R² is Ar¹ orhetAr²; Ar¹ is phenyl substituted with one or more groups independentlyselected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (cyclopropyl)C(═O)NH— and(cyclopropyl)NHC(═O)—, wherein each of said C1-C3 alkyl and C1-C3 alkoxyportions is optionally substituted with 1-3 fluoros; hetAr² is a 6-10membered heteroaryl ring having 1-2 ring nitrogen atoms, wherein saidring is optionally substituted with one or more groups independentlyselected from halogen, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—,(C1-C3 alkyl)C(═O)NH—, (C3-C4 cycloalkyl)C(═O)NH— and (C3-C4cycloalkyl)NHC(═O)—, wherein each of said C1-C3 alkyl and C1-C3 alkoxyportions is optionally substituted with 1-3 fluoros; R³ is H, C1-C4alkyl or (C3-C4)cycloalkyl; and R^(a), R^(b), R^(c) and R^(d) areindependently hydrogen or C1-C6 alkyl optionally substituted with F, OHor C1-C6 alkoxy. 32.-36. (canceled)
 37. The method of claim 31, whereinthe step of determining if the cancer in the patient is anFGFR-associated cancer includes performing an assay to detectdysregulation in a FGFR gene, a FGFR protein, or expression or activityor level of any of the same in a sample from the patient. 38.-42.(canceled)
 43. The method of claim 37, wherein the dysregulation in aFGFR gene, a FGFR protein, or expression or activity or level of any ofthe same is one or more point mutations in the FGFR gene. 44.-51.(canceled)
 52. The method of claim 37, wherein the dysregulation in aFGFR gene, a FGFR protein, or expression or activity or level of any ofthe same, is a chromosome translocation that results in the expressionof a FGFR fusion protein. 53.-55. (canceled)
 56. The method of claim 31,wherein the FGFR-associated cancer is selected from the group consistingof: urothelial carcinoma, breast carcinoma or cancer, endometriodendometrial cancer or endometrial cancer, ovarian carcinoma or cancer,brain cancer, cholangiocarcinoma or intrahepatic cholangiocarinoma,gastric or stomach cancer, gastrointestinal stromal tumors, lung cancer,pancreatic cancer, prostate cancer, colorectal carcinoma or cancer,rectal cancer, renal cell carcinoma, neuroendocrine carcinoma, head andneck (squamous) carcinoma or head and neck adenoid cystic carcinoma,skin cancer, leiomyosarcoma, sarcoma, osteosarcoma, bladder cancer,rhabdomyosarcoma or embryonal rhabdosarcoma, esophageal cancer,hepatocellular carcinoma or liver cancer, salivary gland tumors,glioblatoma multiforme, myxoid lipocarcinoma, oral cancer, thyroidcancer or carcinoma, anaplastic thyroid carcinoma, adenoid cysticcarcinoma, glioblastoma multiforme, myeloproliferativedisorder/hematological malignancy, phosphaturic mesenchymal tumor,cervical cancer, biliary tract cancer, gallbladder cancer, spermatocyticseminoma, seborrheic keratosis, testicular cancer, fallopian tubecarcinoma, carcinoma of unknown primary, gastroesophageal junctioncarcinoma, anal squamous cell carcinoma, hemangioendothelioma, uterinecarcinosarcoma or uterine cancer, carcinoid, peritoneal carcinoma,adrenal carcinoma, bone cancer, peripheral nerve sheath tumor, glioma orparaganglioma, rosette forming glioneural tumor, lymphoepithelioma,mesothelioma, dysembryoplastic neuroepithelial tumor, anddedifferentiated liposarcoma. 57.-163. (canceled)
 164. The method ofclaim 28, wherein X is N.
 165. The method of claim 28, wherein X is CH.166. The method of claim 28, wherein R² is Ar¹.
 167. The method of claim28, wherein R² is HetAr².
 168. The method of claim 28, wherein Ring A ispyrazolyl.
 169. The method of claim 28, wherein R³ is hydrogen.
 170. Themethod of claim 28, wherein the compound of general Formula I isselected from any one of Examples 1-83 or a pharmaceutically acceptablesalt thereof.
 171. The method of claim 28, wherein the cancer isselected from the group consisting of: urothelial carcinoma, breastcarcinoma or cancer, endometriod endometrial cancer or endometrialcancer, ovarian carcinoma or cancer, brain cancer, cholangiocarcinoma orintrahepatic cholangiocarinoma, gastric or stomach cancer,gastrointestinal stromal tumors, lung cancer, pancreatic cancer,prostate cancer, colorectal carcinoma or cancer, rectal cancer, renalcell carcinoma, neuroendocrine carcinoma, head and neck (squamous)carcinoma or head and neck adenoid cystic carcinoma, skin cancer,leiomyosarcoma, sarcoma, osteosarcoma, bladder cancer, rhabdomyosarcomaor embryonal rhabdosarcoma, esophageal cancer, hepatocellular carcinomaor liver cancer, salivary gland tumors, glioblatoma multiforme, myxoidlipocarcinoma, oral cancer, thyroid cancer or carcinoma, anaplasticthyroid carcinoma, adenoid cystic carcinoma, glioblastoma multiforme,myeloproliferative disorder/hematological malignancy, phosphaturicmesenchymal tumor, cervical cancer, biliary tract cancer, gallbladdercancer, spermatocytic seminoma, seborrheic keratosis, testicular cancer,fallopian tube carcinoma, carcinoma of unknown primary, gastroesophagealjunction carcinoma, anal squamous cell carcinoma, hemangioendothelioma,uterine carcinosarcoma or uterine cancer, carcinoid, peritonealcarcinoma, adrenal carcinoma, bone cancer, peripheral nerve sheathtumor, glioma or paraganglioma, rosette forming glioneural tumor,lymphoepithelioma, mesothelioma, dysembryoplastic neuroepithelial tumor,and dedifferentiated liposarcoma.
 172. The method of claim 31, wherein Xis N.
 173. The method of claim 31, wherein X is CH.
 174. The method ofclaim 31, wherein R² is Ar¹.
 175. The method of claim 31, wherein R² isHetAr².
 176. The method of claim 31, wherein Ring A is pyrazolyl. 177.The method of claim 31, wherein R³ is hydrogen.
 178. The method of claim31, wherein the compound of general Formula I is selected from any oneof Examples 1-83 or a pharmaceutically acceptable salt thereof.